Modules_Chapter_4chapter_4PsychopharmacologyOutline_Principles_of

Several years ago I spent the academic year in a neurological research center affiliated with the teaching hospital at a medical center. One morning as I was having breakfast, I read a brief item in the newspaper about a man who had been hospitalized for botulism. Later that morning, I attended a weekly meeting during which the chief of neurology discussed interesting cases presented by the neurological residents. I was surprised to see that we would visit the man with botulism.

We entered the intensive care unit and saw that the man was clearly on his way to recovery. His face was pale and his voice was weak, but he was no longer on a respirator. There wasn’t much to see, so we went back to the lounge and discussed his case.

Just before dinner a few days earlier, Mr. F. had opened a jar of asparagus that his family had canned. He noted right away that it smelled funny. Because his family had grown the asparagus in their own garden, he was reluctant to throw it away. However, he decided that he wouldn’t take any chances. He dipped a spoon into the liquid in the jar and touched it to his tongue. It didn’t taste right, so he didn’t swallow it. Instead, he stuck his tongue out and rinsed it under a stream of water from the faucet at the kitchen sink. He dumped the asparagus into the garbage disposal.

About an hour later, as the family was finishing dinner, Mr. F. discovered that he was seeing double. Alarmed, he asked his wife to drive him to the hospital. When he arrived at the emergency room, he was seen by one of the neurological residents, who asked him, “Mr. F., you haven’t eaten some home-canned foods recently, have you?”

Learning that he had indeed let some liquid from a suspect jar of asparagus touch his tongue, the resident ordered a vial of botulinum antitoxin from the pharmacy. Meanwhile, he took a blood sample from Mr. F.’s vein and sent it to the lab for some in vivo testing in mice. He then administered the antitoxin to Mr. F., but already he could see that it was too late: The patient was showing obvious signs of muscular weakness and was having some difficulty breathing. He was immediately sent to the intensive care unit, where he was put on a respirator. Although he became completely paralyzed, the life support system did what its name indicates, and he regained control of his muscles.

What fascinated me the most was the in vivo testing procedure for the presence of botulinum toxin in Mr. F.’s blood. Plasma extracted from the blood was injected into several mice, half of which had been pretreated with botulinum antitoxin. The pretreated mice survived; the others died. Just think: Mr. F. had touched only a few drops of the contaminated liquid on his tongue and then rinsed it off immediately, but enough of the toxin entered his bloodstream that a small amount of his blood plasma could kill a mouse. By the way, we will examine the pharmacological effect of botulinum toxin later in this chapter.

Chapter 2 introduced you to the cells of the nervous system, and Chapter 3 described its basic structure. Now it is time to build on this information by introducing the field of psychopharmacology. Psychopharmacology is the study of the effects of drugs on the nervous system and (of course) on behavior. (Pharmakon is the Greek word for “drug.”)

psychopharmacology The study of the effects of drugs on the nervous system and on behavior.

But what is a drug? Like many words, this one has several different meanings. In one context it refers to a medication that we would obtain from a pharmacist—a chemical that has a therapeutic effect on a disease or its symptoms. In another context the word refers to a chemical that people are likely to abuse, such as heroin or cocaine. The meaning that will be used in this book (and the one generally accepted by pharmacologists) is “an exogenous chemical not necessary for normal cellular functioning that significantly alters the functions of certain cells of the body when taken in relatively low doses.” Because the topic of this chapter is psycho pharmacology, we will concern ourselves here only with chemicals that alter the functions of cells within the nervous system. The word exogenous rules out chemical messengers produced by the body, such as neurotransmitters, neuromodulators, or hormones. (Exogenous means “produced from without”—that is, from outside the body.) Chemical messengers produced by the body are not drugs, although synthetic chemicals that mimic their effects are classified as drugs. The definition of a drug also rules out essential nutrients, such as proteins, fats, carbohydrates, minerals, and vitamins that are a necessary constituent of a healthy diet. Finally, it states that drugs are effective in low doses. This qualification is important, because large quantities of almost any substance—even common ones such as table salt—will alter the functions of cells.

As we will see in this chapter, drugs have effects and sites of action. Drug effects are the changes we can observe in an animal’s physiological processes and behavior. For example, the effects of morphine, heroin, and other opiates include decreased sensitivity to pain, slowing of the digestive system, sedation, muscular relaxation, constriction of the pupils, and euphoria. The sites of action of drugs are the points at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells. For example, the sites of action of the opiates are specialized receptors situated in the membrane of some neurons. When molecules of opiates attach to and activate these receptors, the drugs alter the activity of these neurons and produce their effects. This chapter considers both the effects of drugs and their sites of action.

drug effect The changes a drug produces in an animal’s physiological processes and behavior.

sites of action The locations at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells.

Psychopharmacology is an important field of neuroscience. It has been responsible for the development of psychotherapeutic drugs, which are used to treat psychological and behavioral disorders. It has also provided tools that have enabled other investigators to study the functions of cells of the nervous system and the behaviors controlled by particular neural circuits.

This chapter does not contain all this book has to say about the subject of psychopharmacology. Throughout the book you will learn about the use of drugs to investigate the nature of neural circuits involved in the control of perception, memory, and behavior. In addition, Chapters 16 and 17 discuss the use of drugs to study and treat mental disorders such as schizophrenia, depression, and the anxiety disorders, and Chapter 18 discusses the physiology of drug abuse.

Principles of Psychopharmacology

This chapter begins with a description of the basic principles of psychopharmacology: the routes of administration of drugs and their fate in the body. The second section discusses the sites of drug actions. The final section discusses specific neurotransmitters and neuromodulators and the physiological and behavioral effects of specific drugs that interact with them.

Pharmacokinetics

To be effective, a drug must reach its sites of action. To do so, molecules of the drug must enter the body and then enter the bloodstream so that they can be carried to the organ (or organs) on which they act. Once there, they must leave the bloodstream and come into contact with the molecules with which they interact. For almost all of the drugs we are interested in, this means that the molecules of the drug must enter the central nervous system (CNS). Some behaviorally active drugs exert their effects on the peripheral nervous system, but these drugs are less important to us than the drugs that affect cells of the CNS.

Molecules of drugs must cross several barriers to enter the body and find their way to their sites of action. Some molecules pass through these barriers easily and quickly; others do so very slowly. And once molecules of drugs enter the body, they begin to be metabolized—broken down by enzymes—or excreted in the urine (or both). In time, the molecules either disappear or are transformed into inactive fragments. The process by which drugs are absorbed, distributed within the body, metabolized, and excreted is referred to as pharmacokinetics (“movements of drugs”).

pharmacokinetics The process by which drugs are absorbed, distributed within the body, metabolized, and excreted.

ROUTES OF ADMINISTRATION

First, let’s consider the routes by which drugs can be administered. For laboratory animals the most common route is injection. The drug is dissolved in a liquid (or, in some cases, suspended in a liquid in the form of fine particles) and injected through a hypodermic needle. The fastest route is intravenous (IV) injection —injection into a vein. The drug enters the bloodstream immediately and reaches the brain within a few seconds. The disadvantages of IV injections are the increased care and skill they require in comparison to most other forms of injection and the fact that the entire dose reaches the bloodstream at once. If an animal is especially sensitive to the drug, there may be little time to administer another drug to counteract its effects.

intravenous (IV) injection Injection of a substance directly into a vein.

An intraperitoneal (IP) injection is rapid but not as rapid as an IV injection. The drug is injected through the abdominal wall into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs. IP injection is the most common route for administering drugs to small laboratory animals. An intramuscular (IM) injection is made directly into a large muscle, such as those found in the upper arm, thigh, or buttocks. The drug is absorbed into the bloodstream through the capillaries that supply the muscle. If very slow absorption is desirable, the drug can be mixed with another drug (such as ephedrine) that constricts blood vessels and retards the flow of blood through the muscle. A drug can also be injected into the space beneath the skin by means of a subcutaneous (SC) injection . A subcutaneous injection is useful only if small amounts of drug need to be administered, because injecting large amounts would be painful. Some fat-soluble drugs can be dissolved in vegetable oil and administered subcutaneously. In this case, molecules of the drug will slowly leave the deposit of oil over a period of several days. If very slow and prolonged absorption of a drug is desirable, the drug can be formed into a dry pellet or placed in a sealed silicone rubber capsule and implanted beneath the skin.

intraperitoneal (IP) injection ( in tra pair i toe nee ul ) Injection of a substance into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs.

intramuscular (IM) injection Injection of a substance into a muscle.

subcutaneous (SC) injection Injection of a substance into the space beneath the skin.

Oral administration is the most common form of administering medicinal drugs to humans. Because of the difficulty of getting laboratory animals to eat something that does not taste good to them, researchers seldom use this route. Some chemicals cannot be administered orally because they will be destroyed by stomach acid or digestive enzymes or because they are not absorbed from the digestive system into the bloodstream. For example, insulin, a peptide hormone, must be injected. Sublingual administration of certain drugs can be accomplished by placing them beneath the tongue. The drug is absorbed into the bloodstream by the capillaries that supply the mucous membrane that lines the mouth. (Obviously, this method works only with humans, who will cooperate and leave the capsule beneath their tongue.) Nitroglycerine, a drug that causes blood vessels to dilate, is taken sublingually by people who suffer the pains of angina pectoris, caused by obstructions in the coronary arteries.

oral administration Administration of a substance into the mouth so that it is swallowed.

sublingual administration ( sub ling wul ) Administration of a substance by placing it beneath the tongue.

Drugs can also be administered at the opposite end of the digestive tract, in the form of suppositories. Intrarectal administration is rarely used to give drugs to experimental animals. For obvious reasons this process would be difficult with a small animal. In addition, when agitated, small animals such as rats tend to defecate, which would mean that the drug would not remain in place long enough to be absorbed. And I’m not sure I would want to try to administer a rectal suppository to a large animal. Rectal suppositories are most commonly used to administer drugs that might upset a person’s stomach.

intrarectal administration Administration of a substance into the rectum.

The lungs provide another route for drug administration: inhalation . Nicotine, freebase cocaine, and marijuana are usually smoked. In addition, drugs used to treat lung disorders are often inhaled in the form of a vapor or fine mist, and many general anesthetics are gasses that are administered through inhalation. The route from the lungs to the brain is very short, and drugs administered this way have very rapid effects.

inhalation Administration of a vaporous substance into the lungs.

Some drugs can be absorbed directly through the skin, so they can be given by means of topical administration . Natural or artificial steroid hormones can be administered in this way, as can nicotine (as a treatment to make it easier for a person to stop smoking). The mucous membrane lining the nasal passages also provides a route for topical administration. Commonly abused drugs such as cocaine hydrochloride are often sniffed so that they come into contact with the nasal mucosa. This route delivers the drug to the brain very rapidly. (The technical, rarely used name for this route is insufflation. And note that sniffing is not the same as inhalation; when powdered cocaine is sniffed, it ends up in the mucous membrane of the nasal passages, not in the lungs.)

topical administration Administration of a substance directly onto the skin or mucous membrane.

Finally, drugs can be administered directly into the brain. As we saw in Chapter 2 , the blood–brain barrier prevents certain chemicals from leaving capillaries and entering the brain. Some drugs cannot cross the blood–brain barrier. If these drugs are to reach the brain, they must be injected directly into the brain or into the cerebrospinal fluid in the brain’s ventricular system. To study the effects of a drug in a specific region of the brain (for example, in a particular nucleus of the hypothalamus), a researcher will inject a very small amount of the drug directly into the brain. This procedure, known as intracerebral administration , is described in more detail in Chapter 5 . To achieve a widespread distribution of a drug in the brain, a researcher will get past the blood–brain barrier by injecting the drug into a cerebral ventricle. The drug is then absorbed into the brain tissue, where it can exert its effects. This route, intracerebroventricular (ICV) administration , is used very rarely in humans—primarily to deliver antibiotics directly to the brain to treat certain types of infections.

intracerebral administration Administration of a substance directly into the brain.

intracerebroventricular (ICV) administration Administration of a substance into one of the cerebral ventricles.

Figure 4.1 shows the time course of blood levels of a commonly abused drug, cocaine, after intravenous injection, inhalation, oral administration, and sniffing. The amounts received were not identical, but the graph illustrates the relative rapidity with which the drug reaches the blood. (See Figure 4.1 . )

FIGURE 4.1 Cocaine in Blood Plasma

The graph shows the concentration of cocaine in blood plasma after intravenous injection, inhalation, oral administration, and sniffing.

(Adapted from Feldman, R. S., Meyer, J. S., and Quenzer, L. F. Principles of Neuropsychopharmacology. Sunderland, MA: Sinauer Associates, 1997; after Jones, R. T. NIDA Research Monographs, 1990, 99, 30–41.)

ENTRY OF DRUGS INTO THE BRAIN

As we saw, drugs exert their effects only when they reach their sites of action. In the case of drugs that affect behavior, most of these sites are located on or in particular cells in the central nervous system. The previous section described the routes by which drugs can be introduced into the body. With the exception of intracerebral or intracerebroventricular administration, the routes of drug administration vary only in the rate at which a drug reaches the blood plasma (that is, the liquid part of the blood). But what happens next? All the sites of action of drugs of interest to psychopharmacologists lie outside the blood vessels.

The most important factor that determines the rate at which a drug in the bloodstream reaches sites of action within the brain is lipid solubility. The blood–brain barrier is a barrier only for water-soluble molecules. Molecules that are soluble in lipids pass through the cells that line the capillaries in the central nervous system, and they rapidly distribute themselves throughout the brain. For example, diacetylmorphine (more commonly known as heroin) is more lipid soluble than morphine is. Thus, an intravenous injection of heroin produces more rapid effects than does one of morphine. Even though the molecules of the two drugs are equally effective when they reach their sites of action in the brain, the fact that heroin molecules get there faster means that they produce a more intense “rush,” and this explains why drug addicts prefer heroin to morphine.

INACTIVATION AND EXCRETION

Drugs do not remain in the body indefinitely. Many are deactivated by enzymes, and all are eventually excreted, primarily by the kidneys. The liver plays an especially active role in enzymatic deactivation of drugs, but some deactivating enzymes are also found in the blood. The brain also contains enzymes that destroy some drugs. In some cases, enzymes transform molecules of a drug into other forms that themselves are biologically active. Occasionally, the transformed molecule is even more active than the one that is administered. In such cases the effects of a drug can have a very long duration.

Drug Effectiveness

Drugs vary widely in their effectiveness. The effects of a small dose of a relatively effective drug can equal or exceed the effects of larger amounts of a relatively ineffective drug. The best way to measure the effectiveness of a drug is to plot a dose-response curve . To do this, subjects are given various doses of a drug, usually defined as milligrams of drug per kilogram of a subject’s body weight, and the effects of the drug are plotted. Because the molecules of most drugs distribute themselves throughout the blood and then throughout the rest of the body, a heavier subject (human or laboratory animal) will require a larger quantity of a drug to achieve the same concentration as a smaller quantity will produce in a smaller subject. As Figure 4.2 shows, increasingly stronger doses of a drug cause increasingly larger effects until the point of maximum effect is reached. At this point, increasing the dose of the drug does not produce any more effect. (See Figure 4.2 . )

dose-response curve A graph of the magnitude of an effect of a drug as a function of the amount of drug administered.

FIGURE 4.2 A Dose-Response Curve

Increasingly stronger doses of the drug produce increasingly larger effects until the maximum effect is reached. After that point, increments in the dose do not produce any increments in the drug’s effect. However, the risk of adverse side effects increases.

Most drugs have more than one effect. Opiates such as morphine and codeine produce analgesia (reduced sensitivity to pain), but they also depress the activity of neurons in the medulla that control heart rate and respiration. A physician who prescribes an opiate to relieve a patient’s pain wants to administer a dose that is large enough to produce analgesia but not large enough to depress heart rate and respiration—effects that could be fatal. Figure 4.3 shows two dose-response curves, one for the analgesic effects of a painkiller and one for the drug’s depressant effects on respiration. The difference between these curves indicates the drug’s margin of safety. Obviously, the most desirable drugs have a large margin of safety. (See Figure 4.3 . )

FIGURE 4.3 Dose-Response Curves for Morphine

The dose-response curve on the left shows the analgesic effect of morphine, and the curve on the right shows one of the drug’s adverse side effects: its depressant effect on respiration. A drug’s margin of safety is reflected by the difference between the dose-response curve for its therapeutic effects and that for its adverse side effects.

One measure of a drug’s margin of safety is its therapeutic index . This measure is obtained by administering varying doses of the drug to a group of laboratory animals such as mice. Two numbers are obtained: the dose that produces the desired effects in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. The therapeutic index is the ratio of these two numbers. For example, if the toxic dose is five times higher than the effective dose, then the therapeutic index is 5.0. The lower the therapeutic index, the more care must be taken in prescribing the drug. For example, barbiturates have relatively low therapeutic indexes—as low as 2 or 3. In contrast, tranquilizers such as Valium have therapeutic indexes of well over 100. As a consequence, an accidental overdose of a barbiturate is much more likely to have tragic effects than a similar overdose of Valium.

therapeutic index The ratio between the dose that produces the desired effect in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals.

Why do drugs vary in their effectiveness? There are two reasons. First, different drugs—even those with the same behavioral effects—may have different sites of action. For example, both morphine and aspirin have analgesic effects, but morphine suppresses the activity of neurons in the spinal cord and brain that are involved in pain perception, whereas aspirin reduces the production of a chemical involved in transmitting information from damaged tissue to pain-sensitive neurons. Because the drugs act very differently, a given dose of morphine (expressed in terms of milligrams of drug per kilogram of body weight) produces much more pain reduction than the same dose of aspirin does.

The second reason that drugs vary in their effectiveness has to do with the affinity of the drug with its site of action. As we will see in the next major section of this chapter, most drugs of interest to psychopharmacologists exert their effects by binding with other molecules located in the central nervous system—with presynaptic or postsynaptic receptors, with transporter molecules, or with enzymes involved in the production or deactivation of neurotransmitters. Drugs vary widely in their affinity for the molecules to which they attach—the readiness with which the two molecules join together. A drug with a high affinity will produce effects at a relatively low concentration, whereas a drug with a low affinity must be administered in higher doses. Thus, even two drugs with identical sites of action can vary widely in their effectiveness if they have different affinities for their binding sites. In addition, because most drugs have multiple effects, a drug can have high affinities for some of its sites of action and low affinities for others. The most desirable drug has a high affinity for sites of action that produce therapeutic effects and a low affinity for sites of action that produce toxic side effects. One of the goals of research by drug companies is to find chemicals with just this pattern of effects.

affinity The readiness with which two molecules join together.

Effects of Repeated Administration

Often, when a drug is administered repeatedly, its effects will not remain constant. In most cases its effects will diminish—a phenomenon known as tolerance . In other cases a drug becomes more and more effective—a phenomenon known as sensitization .

tolerance A decrease in the effectiveness of a drug that is administered repeatedly.

sensitization An increase in the effectiveness of a drug that is administered repeatedly.

Let’s consider tolerance first. Tolerance is seen in many drugs that are commonly abused. For example, a regular user of heroin must take larger and larger amounts of the drug for it to be effective. And once a person has taken heroin regularly enough to develop tolerance, that individual will suffer withdrawal symptoms if he or she suddenly stops taking the drug. Withdrawal symptoms are primarily the opposite of the effects of the drug itself. For example, heroin produces euphoria; withdrawal from it produces dysphoria—a feeling of anxious misery. (Euphoria and dysphoria mean “easy to bear” and “hard to bear,” respectively.) Heroin produces constipation; withdrawal from it produces nausea and cramping. Heroin produces relaxation; withdrawal from it produces agitation.

withdrawal symptom The appearance of symptoms opposite to those produced by a drug when the drug is administered repeatedly and then suddenly no longer taken.

Withdrawal symptoms are caused by the same mechanisms that are responsible for tolerance. Tolerance is the result of the body’s attempt to compensate for the effects of the drug. That is, most systems of the body, including those controlled by the brain, are regulated so that they stay at an optimal value. When the effects of a drug alter these systems for a prolonged time, compensatory mechanisms begin to produce the opposite reaction, at least partially compensating for the disturbance from the optimal value. These mechanisms account for the fact that more and more of the drug must be taken to achieve a given level of effects. Then, when the person stops taking the drug, the compensatory mechanisms make themselves felt, unopposed by the action of the drug.

Research suggests that there are several types of compensatory mechanisms. As we will see, many drugs that affect the brain do so by binding with receptors and activating them. The first compensatory mechanism involves a decrease in the effectiveness of such binding. Either the receptors become less sensitive to the drug (that is, their affinity for the drug decreases), or the receptors decrease in number. The second compensatory mechanism involves the process that couples the receptors to ion channels in the membrane or to the production of second messengers. After prolonged stimulation of the receptors, one or more steps in the coupling process become less effective. (Of course, both effects can occur.) The details of these compensatory mechanisms are described in Chapter 18 , which discusses the causes and effects of drug abuse.

As we saw, many drugs have several different sites of action and thus produce several different effects. This means that some of the effects of a drug may show tolerance but others may not. For example, barbiturates cause sedation and also depress neurons that control respiration. The sedative effects show tolerance, but the respiratory depression does not. This means that if larger and larger doses of a barbiturate are taken to achieve the same level of sedation, the person begins to run the risk of taking a dangerously large dose of the drug.

Sensitization is, of course, the exact opposite of tolerance: Repeated doses of a drug produce larger and larger effects. Because compensatory mechanisms tend to correct for deviations away from the optimal values of physiological processes, sensitization is less common than tolerance. And some of the effects of a drug may show sensitization while others show tolerance. For example, repeated injections of cocaine become more and more likely to produce movement disorders and convulsions, whereas the euphoric effects of the drug do not show sensitization—and may even show tolerance.

Placebo Effects

A placebo is an innocuous substance that has no specific physiological effect. The word comes from the Latin placere, “to please.” A physician may sometimes give a placebo to anxious patients to placate them. (You can see that the word placate also has the same root.) But although placebos have no specificphysiological effect, it is incorrect to say that they have no effect. If a person thinks that a placebo has a physiological effect, then administration of the placebo may actually produce that effect.

placebo ( pla see boh ) An inert substance that is given to an organism in lieu of a physiologically active drug; used experimentally to control for the effects of mere administration of a drug.

When experimenters want to investigate the behavioral effects of drugs in humans, they must use control groups whose members receive placebos, or they cannot be sure that the behavioral effects they observe were caused by specific effects of the drug. Studies with laboratory animals must also use placebos, even though we need not worry about the animals’ “beliefs” about the effects of the drugs we give them. Consider what you must do to give a rat an intraperitoneal injection of a drug. You reach into the animal’s cage, pick the animal up, hold it in such a way that its abdomen is exposed and its head is positioned to prevent it from biting you, insert a hypodermic needle through its abdominal wall, press the plunger of the syringe, and replace the animal in its cage, being sure to let go of it quickly so that it cannot turn and bite you. Even if the substance you inject is innocuous, the experience of receiving the injection would activate the animal’s autonomic nervous system, cause the secretion of stress hormones, and have other physiological effects. If we want to know what the behavioral effects of a drug are, we must compare the drug-treated animals with other animals who receive a placebo, administered in exactly the same way as the drug. (By the way, a skilled and experienced researcher can handle a rat so gently that it shows very little reaction to a hypodermic injection.)

SECTION SUMMARY: Principles of Psychopharmacology

Psychopharmacology is the study of the effects of drugs on the nervous system and behavior. Drugs are exogenous chemicals that are not necessary for normal cellular functioning that significantly alter the functions of certain cells of the body when taken in relatively low doses. Drugs have effects, physiological and behavioral, and they have sites of action—molecules located somewhere in that body with which they interact to produce these effects.

Pharmacokinetics is the fate of a drug as it is absorbed into the body, circulates throughout the body, and reaches its sites of action. Drugs may be administered by intravenous, intraperitoneal, intramuscular, and subcutaneous injection; they may be administered orally, sublingually, intrarectally, by inhalation, and topically (on skin or mucous membrane); and they may be injected intracerebrally or intracerebroventricularly. Lipid-soluble drugs easily pass through the blood–brain barrier, whereas others pass this barrier slowly or not at all.

The time courses of various routes of drug administration are different. Eventually, drugs disappear from the body. Some are deactivated by enzymes, especially in the liver, and others are simply excreted.

The dose-response curve represents a drug’s effectiveness; it relates the amount administered (usually in milligrams per kilogram of the subject’s body weight) to the resulting effect. Most drugs have more than one site of action and thus more than one effect. The safety of a drug is measured by the difference between doses that produce desirable effects and those that produce toxic side effects. Drugs vary in their effectiveness because of the nature of their sites of actions and the affinity between molecules of the drug and these sites of action.

Repeated administration of a drug can cause either tolerance, often resulting in withdrawal symptoms, or sensitization. Tolerance can be caused by decreased affinity of a drug with its receptors, by decreased numbers of receptors, or by decreased coupling of receptors with the biochemical steps it controls. Some of the effects of a drug may show tolerance, while others may not—or may even show sensitization.

■ THOUGHT QUESTIONS

Choose a drug whose effects you are familiar with and suggest where in the body the sites of action of that drug might be.

Some drugs can cause liver damage if large doses are taken for an extended period of time. What aspect of the pharmacokinetics of these drugs might cause the liver damage?

Sites of Drug Action

Throughout the history of our species, people have discovered that plants—and some animals—produce chemicals that act on the nervous system. (Of course, the people who discovered these chemicals knew nothing about neurons and synapses.) Some of these chemicals have been used for their pleasurable effects; others have been used to treat illness, reduce pain, or poison other animals (or enemies). More recently, scientists have learned to produce completely artificial drugs, some with potencies far greater than those of the naturally occurring drugs. The traditional uses of drugs remain, but in addition they can be used in research laboratories to investigate the operations of the nervous system. Most drugs that affect behavior do so by affecting synaptic transmission. Drugs that affect synaptic transmission are classified into two general categories. Those that block or inhibit the postsynaptic effects are called antagonists . Those that facilitate them are called agonists . (The Greek word agon means “contest.” Thus, an agonist is one who takes part in the contest.)

antagonist A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell.

agonist A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell.

This section will describe the basic effects of drugs on synaptic activity. Recall from Chapter 2 that the sequence of synaptic activity goes like this: Neurotransmitters are synthesized and stored in synaptic vesicles. The synaptic vesicles travel to the presynaptic membrane, where they become docked. When an axon fires, voltage-dependent calcium channels in the presynaptic membrane open, permitting the entry of calcium ions. The calcium ions interact with the docking proteins and initiate the release of the neurotransmitters into the synaptic cleft. Molecules of the neurotransmitter bind with postsynaptic receptors, causing particular ion channels to open, which produces excitatory or inhibitory postsynaptic potentials. The effects of the neurotransmitter are kept relatively brief by their reuptake by transporter molecules in the presynaptic membrane or by their destruction by enzymes. In addition, the stimulation of presynaptic autoreceptors on the terminal buttons regulates the synthesis and release of the neurotransmitter. The discussion of the effects of drugs in this section follows the same basic sequence. All of the effects I will describe are summarized in Figure 4.4 , with some details shown in additional figures. I should warn you that some of the effects are complex, so the discussion that follows bears careful reading. I recommend that you Simulate actions of drugs on MyPsychLab, which reviews this material.

Effects on Production of Neurotransmitters

The first step is the synthesis of the neurotransmitter from its precursors. In some cases the rate of synthesis and release of a neurotransmitter is increased when a precursor is administered; in these cases the precursor itself serves as an agonist. (See step 1 in Figure 4.4 . )

The steps in the synthesis of neurotransmitters are controlled by enzymes. Therefore, if a drug inactivates one of these enzymes, it will prevent the neurotransmitter from being produced. Such a drug serves as an antagonist. (See step 2 in Figure 4.4 . )

FIGURE 4.4 Drug Effects on Synaptic Transmission

The figure summarizes the ways in which drugs can affect the synaptic transmission (AGO = agonist; ANT = antagonist; NT = neurotransmitter). Drugs that act as agonists are marked in blue; drugs that act as antagonists are marked in red.

Effects on Storage and Release of Neurotransmitters

Neurotransmitters are stored in synaptic vesicles, which are transported to the presynaptic membrane, where the chemicals are released. The storage of neurotransmitters in vesicles is accomplished by the same kind of transporter molecules that are responsible for reuptake of a neurotransmitter into a terminal button. The transporter molecules are located in the membrane of synaptic vesicles, and their action is to pump molecules of the neurotransmitter across the membrane, filling the vesicles. Some of the transporter molecules that fill synaptic vesicles are capable of being blocked by a drug. Molecules of the drug bind with a particular site on the transporter and inactivate it. Because the synaptic vesicles remain empty, nothing is released when the vesicles eventually rupture against the presynaptic membrane. The drug serves as an antagonist. (See step 3 in Figure 4.4 . )

Some drugs act as antagonists by preventing the release of neurotransmitters from the terminal button. They do so by deactivating the proteins that cause docked synaptic vesicles to fuse with the presynaptic membrane and expel their contents into the synaptic cleft. Other drugs have just the opposite effect: They act as agonists by binding with these proteins and directly triggering release of the neurotransmitter. (See steps 4 and 5 in Figure 4.4 . )

Effects on Receptors

The most important—and most complex—site of action of drugs in the nervous system is on receptors, both presynaptic and postsynaptic. Let’s consider postsynaptic receptors first. (Here is where the careful reading should begin.) Once a neurotransmitter is released, it must stimulate the postsynaptic receptors. Some drugs bind with these receptors, just as the neurotransmitter does. Once a drug has bound with the receptor, it can serve as either an agonist or an antagonist.

A drug that mimics the effects of a neurotransmitter acts as a direct agonist . Molecules of the drug attach to the binding site to which the neurotransmitter normally attaches. This binding causes ion channels controlled by the receptor to open, just as they do when the neurotransmitter is present. Ions then pass through these channels and produce postsynaptic potentials. (See step 6 in Figure 4.4 . )

direct agonist A drug that binds with and activates a receptor.

Drugs that bind with postsynaptic receptors can also serve as antagonists. Molecules of such drugs bind with the receptors but do not open the ion channel. Because they occupy the receptor’s binding site, they prevent the neurotransmitter from opening the ion channel. These drugs are called receptor blockers or direct antagonists . (See step 7 in Figure 4.4 . )

receptor blocker A drug that binds with a receptor but does not activate it; prevents the natural ligand from binding with the receptor.

direct antagonist A synonym for receptor blocker.

FIGURE 4.5 Drug Actions at Binding Sites

(a) Competitive binding: Direct agonists and antagonists act directly on the neurotransmitter binding site. (b) Noncompetitive binding: Indirect agonists and antagonists act on an alternative binding site and modify the effects of the neurotransmitter on opening of the ion channel.

Some receptors have multiple binding sites, to which different ligands can attach. Molecules of the neurotransmitter bind with one site, and other substances (such as neuromodulators and various drugs) bind with the others. Binding of a molecule with one of these alternative sites is referred to as noncompetitive binding , because the molecule does not compete with molecules of the neurotransmitter for the same binding site. If a drug attaches to one of these alternative sites and prevents the ion channel from opening, the drug is said to be an indirect antagonist . The ultimate effect of an indirect antagonist is similar to that of a direct antagonist, but its site of action is different. If a drug attaches to one of the alternative sites and facilitates the opening of the ion channel, it is said to be an indirect agonist . (See Figure 4.5 . )

noncompetitive binding Binding of a drug to a site on a receptor; does not interfere with the binding site for the principal ligand.

indirect antagonist A drug that attaches to a binding site on a receptor and interferes with the action of the receptor; does not interfere with the binding site for the principal ligand.

indirect agonist A drug that attaches to a binding site on a receptor and facilitates the action of the receptor; does not interfere with the binding site for the principal ligand.

FIGURE 4.6 Presynaptic Heteroreceptors

Presynaptic facilitation is caused by activation of receptors that facilitate the opening of calcium channels near the active zone of the postsynaptic terminal button, which promotes release of the neurotransmitter. Presynaptic inhibition is caused by activation of receptors that inhibit the opening of these calcium channels.

As we saw in Chapter 2 , the presynaptic membranes of some neurons contain autoreceptors that regulate the amount of neurotransmitter that is released. Because stimulation of these receptors causes less neurotransmitter to be released, drugs that selectively activate presynaptic receptors act as antagonists. Drugs that block presynaptic autoreceptors have the opposite effect: They increase the release of the neurotransmitter, acting as agonists. (Refer to steps 8 and 9 in Figure 4.4 . )

We also saw in Chapter 2 that some terminal buttons form axoaxonic synapses—synapses of one terminal button with another. Activation of the first terminal button causes presynaptic inhibition or facilitation of the second one. The second terminal button contains presynaptic heteroreceptors , which are sensitive to the neurotransmitter released by the first one. (Auto means “self”; hetero means “other.”) Presynaptic heteroreceptors that produce presynaptic inhibition do so by inhibiting the release of the neurotransmitter. Conversely, presynaptic heteroreceptors responsible for presynaptic facilitation facilitate the release of the neurotransmitter. So drugs can block or facilitate presynaptic inhibition or facilitation, depending on whether they block or activate presynaptic heteroreceptors. (See Figure 4.6 . )

presynaptic heteroreceptor A receptor located in the membrane of a terminal button that receives input from another terminal button by means of an axoaxonic synapse; binds with the neurotransmitter released by the presynaptic terminal button.

Finally (yes, this is the last site of action I will describe in this subsection), you will recall from Chapter 2 that autoreceptors are located in the membrane of dendrites of some neurons. When these neurons become active, their dendrites, as well as their terminal buttons, release neurotransmitter. The neurotransmitter released by the dendrites stimulates autoreceptors located on these same dendrites, which decrease neural firing by producing hyperpolarizations. This mechanism has a regulatory effect, serving to prevent these neurons from becoming too active. Thus, drugs that bind with and activatedendritic autoreceptors will serve as antagonists. Those that bind with and block dendritic autoreceptors will serve as agonists, because they will prevent the inhibitory hyperpolarizations. (See Figure 4.7 . )

As you will surely realize, the effects of a particular drug that binds with a particular type of receptor can be very complex. The effects depend on where the receptor is located, what its normal effects are, and whether the drug activates the receptor or blocks its actions.

FIGURE 4.7 Dendritic Autoreceptors

The dendrites of certain neurons release some neurotransmitter when the cell is active. Activation of dendritic autoreceptors by the neurotransmitter (or by a drug that binds with these receptors) hyperpolarizes the membrane, reducing the neuron’s rate of firing. Blocking of dendritic autoreceptors by a drug prevents this effect.

Effects on Reuptake or Destruction of Neurotransmitters

The next step after stimulation of the postsynaptic receptor is termination of the postsynaptic potential. Two processes accomplish that task: Molecules of the neurotransmitter are taken back into the terminal button through the process of reuptake, or they are destroyed by an enzyme. Drugs can interfere with either of these processes. In the first case, molecules of the drug attach to the transporter molecules responsible for reuptake and inactivate them, thus blocking reuptake. In the second case, molecules of the drug bind with the enzyme that normally destroys the neurotransmitter and prevents the enzymes from working. The most important example of such an enzyme is acetylcholinesterase, which destroys acetylcholine. Because both types of drugs prolong the presence of molecules of the neurotransmitter in the synaptic cleft (and hence in a location where these molecules can stimulate postsynaptic receptors), they serve as agonists. (Refer to steps 10 and 11 in Figure 4.4 . )

SECTION SUMMARY: Sites of Drug Action

The process of synaptic transmission entails the synthesis of the neurotransmitter, its storage in synaptic vesicles, its release into the synaptic cleft, its interaction with postsynaptic receptors, and the consequent opening of ion channels in the postsynaptic membrane. The effects of the neurotransmitter are then terminated by reuptake into the terminal button or by enzymatic deactivation.

Each of the steps necessary for synaptic transmission can be interfered with by drugs that serve as antagonists, and a few can be stimulated by drugs that serve as agonists. Thus, drugs can increase the pool of available precursor, block a biosynthetic enzyme, prevent the storage of neurotransmitter in synaptic vesicles, stimulate or block the release of the neurotransmitter, stimulate or block presynaptic or postsynaptic receptors, retard reuptake, or deactivate enzymes that destroy the neurotransmitter. A drug that activates postsynaptic receptors serves as an agonist, whereas one that activates presynaptic or dendritic autoreceptors serves as an antagonist. A drug that blocks postsynaptic receptors serves as an antagonist, whereas one that blocks autoreceptors serves as an agonist. A drug that activates or blocks presynaptic heteroreceptors serves as an agonist or antagonist, depending on whether the heteroreceptors are responsible for presynaptic facilitation or inhibition.

■ THOUGHT QUESTION

Explain how a drug that blocks receptors can serve as an agonist.

Neurotransmitters and Neuromodulators

Because neurotransmitters have two general effects on postsynaptic membranes—depolarization (EPSP) or hyperpolarization (IPSP)—one might expect that there would be two kinds of neurotransmitters, excitatory and inhibitory. Instead, there are many different kinds—several dozen at least. In the brain most synaptic communication is accomplished by two neurotransmitters: one with excitatory effects (glutamate) and one with inhibitory effects (GABA). (Another inhibitory neurotransmitter, glycine, is found in the spinal cord and lower brain stem.) Most of the activity of local circuits of neurons involves balances between the excitatory and inhibitory effects of these chemicals, which are responsible for most of the information transmitted from place to place within the brain. In fact, there are probably no neurons in the brain that do not receive excitatory input from glutamate-secreting terminal buttons and inhibitory input from neurons that secrete either GABA or glycine. And with the exception of neurons that detect painful stimuli, all sensory organs transmit information to the brain through axons whose terminals release glutamate. (Pain-detecting neurons secrete a peptide.)

What do all the other neurotransmitters do? In general, they have modulating effects rather than information-transmitting effects. That is, the release of neurotransmitters other than glutamate and GABA tends to activate or inhibit entire circuits of neurons that are involved in particular brain functions. For example, secretion of acetylcholine activates the cerebral cortex and facilitates learning, but the information that is learned and remembered is transmitted by neurons that secrete glutamate and GABA. Secretion of norepinephrine increases vigilance and enhances readiness to act when a signal is detected. Secretion of histamine enhances wakefulness. Secretion of serotonin suppresses certain categories of species-typical behaviors and reduces the likelihood that the animal acts impulsively. Secretion of dopamine in some regions of the brain generally activates voluntary movements but does not specify which movements will occur. In other regions, secretion of dopamine reinforces ongoing behaviors and makes them more likely to occur at a later time. Because particular drugs can selectively affect neurons that secrete particular neurotransmitters, they can have specific effects on behavior.

This section introduces the most important neurotransmitters, discusses some of their behavioral functions, and describes the drugs that interact with them. As we saw in the previous section of this chapter, drugs have many different sites of action. Fortunately for your information-processing capacity (and perhaps your sanity), not all types of neurons are affected by all types of drugs. As you will see, that still leaves a good number of drugs to be mentioned by name. Obviously, some are more important than others. Those whose effects I describe in some detail are more important than those I mention in passing.

Acetylcholine

Acetylcholine is the primary neurotransmitter secreted by efferent axons of the peripheral nervous system. All muscular movement is accomplished by the release of acetylcholine, and ACh is also found in the ganglia of the autonomic nervous system and at the target organs of the parasympathetic branch of the ANS. Because ACh is found outside the central nervous system in locations that are easy to study, this neurotransmitter was the first to be discovered, and it has received much attention from neuroscientists. Some terminology: These synapses are said to be acetylcholinergic. Ergon is the Greek word for “work.” Thus, dopaminergic synapses release dopamine, serotonergic synapses release serotonin, and so on. (The suffix -ergic is pronounced “ ur jik”.)

The axons and terminal buttons of acetylcholinergic neurons are distributed widely throughout the brain. Three systems have received the most attention from neuroscientists: those originating in the dorsolateral pons, the basal forebrain, and the medial septum. The effects of ACh release in the brain are generally facilitatory. The acetylcholinergic neurons located in the dorsolateral pons play a role in REM sleep (the phase of sleep during which dreaming occurs). Those located in the basal forebrain are involved in activating the cerebral cortex and facilitating learning, especially perceptual learning. Those located in the medial septum control the electrical rhythms of the hippocampus and modulate its functions, which include the formation of particular kinds of memories.

Figure 4.8 shows a schematic midsagittal view of a rat brain. On it are indicated the most important sites of acetylcholinergic cell bodies and the regions served by the branches of their axons. The figure illustrates a rat brain because most of the neuroanatomical tracing studies have been performed with rats. Presumably, the location and projections of acetylcholinergic neurons in the human brain resemble those found in the rat brain, but we cannot yet be certain. The methods used for tracing particular systems of neurons in the brain and the difficulty of doing such studies with the human brain are described in Chapter 5 . (See Figure 4.8 . )

Acetylcholine is composed of two components: choline, a substance derived from the breakdown of lipids, and acetate, the anion found in vinegar, also called acetic acid. Acetate cannot be attached directly to choline; instead, it is transferred from a molecule of acetyl-CoA. CoA (coenzyme A) is a complex molecule, consisting in part of the vitamin pantothenic acid (one of the B vitamins). CoA is produced by the mitochondria, and it takes part in many reactions in the body. Acetyl-CoA is simply CoA with an acetate ion attached to it. ACh is produced by the following reaction: In the presence of the enzyme choline acetyltransferase (ChAT) , the acetate ion is transferred from the acetyl-CoA molecule to the choline molecule, yielding a molecule of ACh and one of ordinary CoA. (See Figure 4.9 . )

acetyl-CoA ( a see tul ) A cofactor that supplies acetate for the synthesis of acetylcholine.

choline acetyltransferase (ChAT) (koh leen a see tul trans fer ace ) The enzyme that transfers the acetate ion from acetyl coenzyme A to choline, producing the neurotransmitter acetylcholine.

FIGURE 4.8 Acetylcholinergic Pathways in a Rat Brain

This schematic figure shows the locations of the most important groups of acetylcholinergic neurons and the distribution of their axons and terminal buttons.

(Adapted from Woolf, N. J. Progress in Neurobiology, 1991, 37, 475–524.)

FIGURE 4.9 Biosynthesis of Acetylcholine

A simple analogy will illustrate the role of coenzymes in chemical reactions. Think of acetate as a hot dog and choline as a bun. The task of the person (enzyme) who operates the hot dog vending stand is to put a hot dog into the bun (make acetylcholine). To do so, the vendor needs a fork (coenzyme) to remove the hot dog from the boiling water. The vendor inserts the fork into the hot dog (attaches acetate to CoA) and transfers the hot dog from fork to bun.

Two drugs, botulinum toxin and the venom of the black widow spider, affect the release of acetylcholine. Botulinum toxin is produced by clostridium botulinum, a bacterium that can grow in improperly canned food. This drug prevents the release of ACh (step 5 of Figure 4.4 ). As we saw in this chapter’s opening case, botulinum toxin drug is an extremely potent poison because the paralysis it can cause leads to suffocation. In contrast, black widow spider venom has the opposite effect: It stimulates the release of ACh (step 4 of Figure 4.4 ). Although the effects of black widow spider venom can also be fatal, the venom is much less toxic than botulinum toxin. In fact, most healthy adults would have to receive several bites, but infants or frail elderly people would be more susceptible.

botulinum toxin ( bot you lin um ) An acetylcholine antagonist; prevents release by terminal buttons.

black widow spider venom A poison produced by the black widow spider that triggers the release of acetylcholine.

FIGURE 4.10 Destruction of Acetylcholine (ACh) by Acetylcholinesterase (AChE)

You may have been wondering why double vision was the first symptom of botulism in the opening case. The answer is that the delicate balance among the muscles that move the eyes is upset by any interference with acetylcholinergic transmission. You undoubtedly know that botox treatment has become fashionable. A very dilute (obviously!) solution of botulinum toxin is injec ted into people’s facial muscles to stop muscular contractions that are causing wrinkles in the skin. I’m not planning on getting a botox treatment, but if I did, I would want to be sure that the solution was sufficiently dilute.

You will recall from Chapter 2 that after being released by the terminal button, ACh is deactivated by the enzyme acetylcholinesterase (AChE), which is present in the postsynaptic membrane. (See Figure 4.10 . )

Drugs that deactivate AChE (step 11 of Figure 4.4 ) are used for several purposes. Some are used as insectici des. These drugs readily kill insects but not humans and other mammals, because our blood contains enzymes that destroy them. (Insects lack the enzyme.) Other AChE inhibitors are used medically. For example, a hereditary disorder called myasthenia gravis is caused by an attack of a person’s immune system against acetylch oline receptors located on skeletal muscles. (Kathryn D., whose symptoms were described in the opening case of Chapter 2 , had this disorder.) The person becomes weaker and weaker as the muscles become less responsive to the neurotransmitter. If the person is given an AChE inhibitor such as neostigmine , the person will regain some strength because the acetylcholine that is released has a more prolonged effect on the remaining receptors. (Neostigmine cannot cross the blood–brain barrier, so it does not affect the AChE found in the central nervous system.)

neostigmine ( nee o stig meen ) A drug that inhibits the activity of acetylcholinesterase.

There are two types of ACh receptors: one ionotropic and one metabotropic. These receptors were identified when investigators discovered that different drugs activated them (step 6 of Figure 4.4 ). The ionotropic ACh receptor is stimulated by nicotine, a drug found in tobacco leaves. (The Latin name of the plant is Nicotiniana tabacum.) The metabotropic ACh receptor is stimulated by muscarine, a drug found in the poison mushroom Amanita muscaria. Consequently, these two ACh receptors are referred to as nicotinic receptors and muscarinic receptors , respectively. Because muscle fibers must be able to contract rapidly, they contain the rapid, ionotropic nicotinic receptors.

nicotinic receptor An ionotropic acetylcholine receptor that is stimulated by nicotine and blocked by curare.

muscarinic receptor ( muss ka rin ic ) A metabotropic acetylcholine receptor that is stimulated by muscarine and blocked by atropine.

Because muscarinic receptors are metabotropic in nature and thus control ion channels through the production of second messengers, their actions are slower and more prolonged than those of nicotinic receptors. The central nervous system contains both kinds of ACh receptors, but muscarinic receptors predominate. Some nicotinic receptors are found at axoaxonic synapses in the brain, where they produce presynaptic facilitation. Activation of these receptors is responsible for the addictive effect of the nicotine found in tobacco smoke.

Just as two different drugs stimulate the two classes of acetylcholine receptors, two different drugs blockthem (step 7 of Figure 4.4 ). Both drugs were discovered in nature long ago, and both are still used by modern medicine. The first, atropine , blocks muscarinic receptors. The drug is named after Atropos, the Greek fate who cut the thread of life (which a sufficient dose of atropine will certainly do). Atropine is one of several belladonna alkaloids extracted from a plant called the deadly nightshade, and therein lies a tale. Many years ago, women who wanted to increase their attractiveness to men put drops containing belladonna alkaloids into their eyes. In fact, belladonna means “pretty lady.” Why was the drug used this way? One of the unconscious responses that occurs when we are interested in something is dilation of our pupils. By blocking the effects of acetylcholine on the pupil, belladonna alkaloids such as atropine make the pupils dilate. This change makes a woman appear more interested in a man when she looks at him, and, of course, this apparent sign of interest makes him regard her as more attractive.

atropine (a tro peen) A drug that blocks muscarinic acetylcholine receptors.

Another drug, curare , blocks nicotinic receptors. Because these receptors are the ones found on muscles, curare, like botulinum toxin, causes paralysis. However, the effects of curare are much faster. The drug is extracted from several different species of plants found in South America, where it was discovered long ago by people who used it to coat the tips of arrows and darts. Within minutes of being struck by one of these points, an animal collapses, ceases breathing, and dies. Nowadays, curare (and other drugs with the same site of action) are used to paralyze patients who are to undergo surgery so that their muscles will relax completely and not contract when they are cut with a scalpel. An anesthetic must also be used, because a person who receives only curare will remain perfectly conscious and sensitive to pain, even though paralyzed. And, of course, a respirator must be used to supply air to the lungs.

curare (kew rahr ee) A drug that blocks nicotinic acetylcholine receptors.

The Monoamines

Dopamine, norepinephrine, epinephrine, serotonin, and histamine are five chemicals that belong to a family of compounds called monoamines . Because the molecular structures of these substances are similar, some drugs affect the activity of all of them to some degree. The first three—dopamine, norepinephrine, and epinephrine—belong to a subclass of monoamines called catecholamines . It is worthwhile learning the terms in Table 4.1 , because they will be used throughout the rest of this book. (See Table 4.1 . )

monoamine (mahn o a meen ) A class of amines that includes indolamines, such as serotonin; and catecholamines, such as dopamine, norepinephrine, and epinephrine.

catecholamine ( cat a kohl a meen ) A class of amines that includes the neurotransmitters dopamine, norepinephrine, and epinephrine.

The monoamines are produced by several systems of neurons in the brain. Most of these systems consist of a relatively small number of cell bodies located in the brain stem, whose axons branch repeatedly and give rise to an enormous number of terminal buttons distributed throughout many regions of the brain. Monoaminergic neurons thus serve to modulate the function of widespread regions of the brain, increasing or decreasing the activities of particular brain functions.

DOPAMINE

TABLE 4.1 Classification of the Monoamine Neurotransmitters

Catecholamines	Indolamine	Ethylamine
Dopamine	Serotonin	Histamine
Norepinephrine
Epinephrine

The first catecholamine in Table 4.1 , dopamine (DA) , produces both excitatory and inhibitory postsynaptic potentials, depending on the postsynaptic receptor. Dopamine is one of the more interesting neurotransmitters because it has been implicated in several important functions, including movement, attention, learning, and the reinforcing effects of drugs that people tend to abuse. It is discussed in Chapters 8 , 9 , 13 , 16 , and 18 . The synthesis of the catecholamines is somewhat more complicated than that of ACh, but each step is a simple one. The precursor molecule is modified slightly, step by step, until it achieves its final shape. Each step is controlled by a different enzyme, which causes a small part to be added or taken off. The precursor for the two major catecholamine neurotransmitters (dopamine and norepinephrine) is tyrosine, an essential amino acid that we must obtain from our diet. Tyrosine receives a hydroxyl group (OH—an oxygen atom and a hydrogen atom) and becomes L-DOPA (L-3,4-dihydroxyphenylalanine). The enzyme that adds the hydroxyl group is called tyrosine hydroxylase. L-DOPA then loses a carboxyl group (COOH—one carbon atom, two oxygen atoms, and one hydrogen atom) through the activity of the enzyme DOPA decarboxylase and becomes dopamine. Finally, the enzyme dopamine β-hydroxylase attaches a hydroxyl group to dopamine, which becomes norepinephrine. These reactions are shown in Figure 4.11 .

dopamine (DA) (dope a meen ) A neurotransmitter; one of the catecholamines.

L-DOPA ( ell dope a ) The levorotatory form of DOPA; the precursor of the catecholamines; often used to treat Parkinson’s disease because of its effect as a dopamine agonist.

The brain contains several systems of dopaminergic neurons. The three most important of these originate in the midbrain: in the substantia nigra and in the ventral tegmental area. (The substantia nigra was shown in Figure 3.21 ; the ventral tegmental area is located just below this region.) The cell bodies of neurons of the nigrostriatal system are located in the substantia nigra and project their axons to the neostriatum: the caudate nucleus and the putamen. The neostriatum is an important part of the basal ganglia, which is involved in the control of movement. The cell bodies of neurons of the mesolimbic system are located in the ventral tegmental area and project their axons to several parts of the limbic system, including the nucleus accumbens, amygdala, and hippocampus. The nucleus accumbens plays an important role in the reinforcing (rewarding) effects of certain categories of stimuli, including those of drugs that people abuse. The cell bodies of neurons of the mesocortical system are also located in the ventral tegmental area. Their axons project to the prefrontal cortex. These neurons have an excitatory effect on the frontal cortex and affect such functions as formation of short-term memories, planning, and strategy preparation for problem solving. These three systems of dopaminergic neurons are shown in Figure 4.12 .

nigrostriatal system ( nigh grow stry ay tul ) A system of neurons originating in the substantia nigra and terminating in the neostriatum (caudate nucleus and putamen).

mesolimbic system ( mee zo lim bik ) A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus.

mesocortical system ( mee zo kor ti kul ) A system of dopaminergic neurons originating in the ventral tegmental area and terminating in the prefrontal cortex.

FIGURE 4.11 Biosynthesis of the Catecholamines

Degeneration of dopaminergic neurons that connect the substantia nigra with the caudate nucleus causes Parkinson’s disease , a movement disorder characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements. The cell bodies of these neurons are located in a region of the brain called the substantia nigra (“black substance”). This region is normally stained black with melanin, the substance that gives color to skin. This compound is produced by the breakdown of dopamine. (The brain damage that causes Parkinson’s disease was discovered by pathologists who observed that the substantia nigra of a deceased person who had had this disorder was pale rather than black.) People with Parkinson’s disease are given L-DOPA, the precursor to dopamine. Although dopamine cannot cross the blood–brain barrier, L-DOPA can. Once L-DOPA reaches the brain, it is taken up by dopaminergic neurons and is converted to dopamine (step 1 of Figure 4.4 ). The increased synthesis of dopamine causes more dopamine to be released by the surviving dopaminergic neurons in patients with Parkinson’s disease. As a consequence, the patients’ symptoms are alleviated.

Parkinson’s disease A neurological disease characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movements; caused by degeneration of the nigrostriatal system.

Another drug, AMPT (or α-methyl-p-tyrosine), inactivates tyrosine hydroxylase, the enzyme that converts tyrosine to L-DOPA (step 2 of Figure 4.4 ). Because this drug interferes with the synthesis of dopamine (and of norepinephrine as well), it serves as a catecholamine antagonist. The drug is not normally used medically, but it has been used as a research tool in laboratory animals.

AMPT A drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of the catecholamines.

The drug reserpine prevents the storage of monoamines in synaptic vesicles by blocking the transporters in the membrane of vesicles of monoaminergic neurons (step 3 of Figure 4.4 ). Because the synaptic vesicles remain empty, no neurotransmitter is released when an action potential reaches the terminal button. Reserpine, then, is a monoamine antagonist. The drug, which comes from the root of a shrub, was discovered over 3000 years ago in India, where it was found to be useful in treating snakebite and seemed to have a calming effect. Pieces of the root are still sold in markets in rural areas of India. In Western medicine, reserpine was previously used to treat high blood pressure, but it has been replaced by drugs with fewer side effects.

reserpine ( ree sur peen ) A drug that interferes with the storage of monoamines in synaptic vesicles.

Several different types of dopamine receptors have been identified, all metabotropic. Of these, two are the most common: D1 receptors and D2 receptors. It appears that D1 receptors are exclusively postsynaptic, whereas D2 receptors are found both presynaptically and postsynaptically in the brain. Stimulation of D1receptors increases the production of the second messenger cyclic AMP, whereas stimulation of D2receptors decreases it, as does stimulation of D3 and D4 receptors. Several drugs stimulate or block specific types of dopamine receptors.

FIGURE 4.12 Dopaminergic Pathways in a Rat Brain

This schematic figure shows the locations of the most important groups of dopaminergic neurons and the distribution of their axons and terminal buttons.

(Adapted from Fuxe, K., Agnati, L. F., Kalia, M., et al., in Basic and Clinical Aspects of Neuroscience: The Dopaminergic System, edited by E. Fluckinger, E. E. Muller, and M. O. Thomas. Berlin: Springer–Verlag, 1985.)

Autoreceptors are found in the dendrites, soma, and terminal buttons of dopaminergic neurons. Activation of the autoreceptors in the dendritic and somatic membrane decreases neural firing by producing hyperpolarizations. The presynaptic autoreceptors located in the terminal buttons suppress the activity of the enzyme tyrosine hydroxylase and thus decrease the production of dopamine—and ultimately its release. Dopamine autoreceptors resemble D2 receptors, but there seem to be some differences. For example, the drug apomorphine is a D2 agonist, but it seems to have a greater affinity for presynaptic D2 receptors than for postsynaptic D2 receptors. A low dose of apomorphine acts as an antagonist, because it stimulates the presynaptic receptors and inhibits the production and release of dopamine. Higher doses begin to stimulate postsynaptic D2 receptors, and the drug begins to act as a direct agonist. (See Figure 4.13 . )

apomorphine ( ap o more feen ) A drug that blocks dopamine autoreceptors at low doses; at higher doses, blocks postsynaptic receptors as well.

Several drugs inhibit the reuptake of dopamine, thus serving as potent dopamine agonists (step 10 of Figure 4.4 ). The best known of these drugs are amphetamine, cocaine, and methylphenidate. Amphetamine has an interesting effect: It causes the release of both dopamine and norepinephrine by causing the transporters for these neurotransmitters to run in reverse, propelling DA and NE into the synaptic cleft. Of course, this action also blocks reuptake of these neurotransmitters. Cocaine and methylphenidate simply block dopamine reuptake. Because cocaine also blocks voltage-dependent sodium channels, it is sometimes used as a topical anesthetic, especially in the form of eye drops for eye surgery. Methylphenidate (Ritalin) is used to treat children who have attention deficit disorder.

methylphenidate ( meth ul fen i date ) A drug that inhibits the reuptake of dopamine.

The production of the catecholamines is regulated by an enzyme called monoamine oxidase (MAO) . This enzyme is found within monoaminergic terminal buttons, where it destroys excessive amounts of neurotransmitter. A drug called deprenyl destroys the particular form of monoamine oxidase (MAO-B) that is found in dopaminergic terminal buttons. Because deprenyl prevents the destruction of dopamine, more dopamine is released when an action potential reaches the terminal button. Thus, deprenyl serves as a dopamine agonist. (See Figure 4.14 . )

monoamine oxidase (MAO) (mahn o a meen ) A class of enzymes that destroy the monoamines: dopamine, norepinephrine, and serotonin.

deprenyl (depp ra nil ) A drug that blocks the activity of MAO-B; acts as a dopamine agonist.

FIGURE 4.13 Effects of Low and High Doses of Apomorphine

At low doses, apomorphine serves as a dopamine antagonist; at high doses, it serves as an agonist.

MAO is also found in the blood, where it deactivates amines that are present in foods such as chocolate and cheese. Without such deactivation these amines could cause dangerous increases in blood pressure.

Dopamine has been implicated as a neurotransmitter that might be involved in schizophrenia, a serious mental disorder whose symptoms include hallucinations, delusions, and disruption of normal, logical thought processes. Drugs such as chlorpromazine , which block D2 receptors, alleviate these symptoms (step 7 of Figure 4.4 ). Hence, investigators have speculated that schizophrenia is produced by overactivity of dopaminergic neurons. More recently discovered drugs—the so-called atypical antipsychotics—have more complicated actions, which are discussed in Chapter 16 .

chlorpromazine ( klor proh ma zeen ) A drug that reduces the symptoms of schizophrenia by blocking dopamine D2 receptors.

FIGURE 4.14 Role of Monoamine Oxidase

This schematic shows the role of monoamine oxidase in dopaminergic terminal buttons and the action of deprenyl.

FIGURE 4.15 Noradrenergic Pathways in a Rat Brain

This schematic figure shows the locations of the most important groups of noradrenergic neurons and the distribution of their axons and terminal buttons.

(Adapted from Cotman, C. W. and McGaugh, J. L. Behavioral Neuroscience: An Introduction. New York: Academic Press, 1980.)

NOREPINEPHRINE

Because norepinephrine (NE) , like ACh, is found in neurons in the autonomic nervous system, this neurotransmitter has received much experimental attention. I should note that the terms Adrenalin and epinephrine are synonymous, as are noradrenalin and norepinephrine. Let me explain why. Epinephrine is a hormone produced by the adrenal medulla, the central core of the adrenal glands, located just above the kidneys. Epinephrine also serves as a neurotransmitter in the brain, but it is of minor importance compared with norepinephrine. Ad renal is Latin for “toward the kidney.” In Greek, one would say epi nephron (“upon the kidney”), hence the term epinephrine. The latter term has been adopted by pharmacologists, probably because the word Adrenalin was appropriated by a drug company as a proprietary name; therefore, to be consistent with general usage, I will refer to the neurotransmitter as norepinephrine. The accepted adjectival form is noradrenergic; I suppose that norepinephrinergic never caught on because it takes so long to pronounce.

norepinephrine (NE) ( nor epp i neff rin ) One of the catecholamines; a neurotransmitter found in the brain and in the sympathetic division of the autonomic nervous system.

epinephrine ( epp i neff rin ) One of the catecholamines; a hormone secreted by the adrenal medulla; serves also as a neurotransmitter in the brain.

We have already seen the biosynthetic pathway for norepinephrine in Figure 4.11 . The drug AMPT, which prevents the conversion of tyrosine to L-DOPA, blocks the production of norepinephrine as well as dopamine (step 2 of Figure 4.4 ).

Most neurotransmitters are synthesized in the cytoplasm of the terminal button and then stored in newly formed synaptic vesicles. However, for norepinephrine the final step of synthesis occurs inside the vesicles themselves. The vesicles are first filled with dopamine. Then the dopamine is converted to norepinephrine through the action of the enzyme dopamine β-hydroxylase located within the vesicles. The drug fusaric acid inhibits the activity of the enzyme dopamine-β-hydroxylase and thus blocks the production of norepinephrine without affecting the production of dopamine.

fusaric acid ( few sahr ik ) A drug that inhibits the activity of the enzyme dopamine-β-hydroxylase and thus blocks the production of norepinephrine.

Excess norepinephrine in the terminal buttons is destroyed by monoamine oxidase, type A. The drug moclobemide specifically blocks MAO-A and hence serves as a noradrenergic agonist.

moclobemide ( mok low bem ide ) A drug that blocks the activity of MAO-A; acts as a noradrenergic agonist.

Almost every region of the brain receives input from noradrenergic neurons. The cell bodies of most of these neurons are located in seven regions of the pons and medulla and one region of the thalamus. The cell bodies of the most important noradrenergic system begin in the locus coeruleus , a nucleus located in the dorsal pons. The axons of these neurons project to the regions shown in Figure 4.15 . As we will see later, the primary effect of activation of these neurons is an increase in vigilance—attentiveness to events in the environment. (See Figure 4.15 . )

locus coeruleus ( sur oo lee us ) A dark-colored group of noradrenergic cell bodies located in the pons near the rostral end of the floor of the fourth ventricle.

Most neurons that release norepinephrine do not do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through axonal varicosities , beadlike swellings of the axonal branches. These varicosities give the axonal branches of catecholaminergic neurons the appearance of beaded chains.

axonal varicosity An enlarged region along the length of an axon that contains synaptic vesicles and releases a neurotransmitter or neuromodulator.

There are several types of noradrenergic receptors, identified by their differing sensitivities to various drugs. Actually, these receptors are usually called adrenergic receptors rather than noradrenergicreceptors, because they are sensitive to epinephrine (Adrenalin) as well as norepinephrine. Neurons in the central nervous system contain α1- and α2-adrenergic receptors and β1- and β2-adrenergic receptors.All four kinds of receptors are also found in various organs of the body besides the brain and are responsible for the effects of epinephrine and norepinephrine when they act as hormones outside the central nervous system. In the brain, all autoreceptors appear to be of the α2 type. (The drug idazoxan blocks α2 autoreceptors and hence acts as an agonist.) All adrenergic receptors are metabotropic, coupled to G proteins that control the production of second messengers.

idazoxan A drug that blocks presynaptic noradrenergic α2 receptors and hence acts as an agonist, facilitating the synthesis and release of NE.

Adrenergic receptors produce both excitatory and inhibitory effects. In general, the behavioral effects of the release of NE are excitatory. In the brain, α1 receptors produce a slow depolarizing (excitatory) effect on the postsynaptic membrane, while α2 receptors produce a slow hyperpolarization. Both types of b receptors increase the responsiveness of the postsynaptic neuron to its excitatory inputs, which presumably related to the role this neurotransmitter plays in vigilance. Noradrenergic neurons—in particular, α2 receptors—are also involved in sexual behavior and in the control of appetite.

SEROTONIN

The third monoamine neurotransmitter, serotonin (also called 5-HT, or 5-hydroxytryptamine), has also received much experimental attention. Its behavioral effects are complex. Serotonin plays a role in the regulation of mood; in the control of eating, sleep, and arousal; and in the regulation of pain. Serotonergic neurons are involved somehow in the control of dreaming.

serotonin (5-HT) ( sair a toe nin ) An indolamine neurotransmitter; also called 5-hydroxytryptamine.

The precursor for serotonin is the amino acid tryptophan. The enzyme tryptophan hydroxylase adds a hydroxyl group, producing 5-HTP (5-hydroxytryptophan). The enzyme 5-HTP decarboxylase removes a carboxyl group from 5-HTP, and the result is 5-HT (serotonin). (See Figure 4.16 . ) The drug PCPA (p-chlorophenylalanine) blocks the activity of tryptophan hydroxylase and thus serves as a serotonergic antagonist.

PCPA A drug that inhibits the activity of tryptophan hydroxylase and thus interferes with the synthesis of 5-HT.

The cell bodies of serotonergic neurons are found in nine clusters, most of which are located in the raphe nuclei of the midbrain, pons, and medulla. Like norepinephrine, 5-HT is released from varicosities rather than terminal buttons. The two most important clusters of serotonergic cell bodies are found in the dorsal and medial raphe nuclei, and I will restrict my discussion to these clusters. The word raphe means “seam” or “crease” and refers to the fact that most of the raphe nuclei are found at or near the midline of the brain stem. Both the dorsal and median raphe nuclei project axons to the cerebral cortex. In addition, neurons in the dorsal raphe innervate the basal ganglia, and those in the median raphe innervate the dentate gyrus, a part of the hippocampal formation. These and other connections are shown in Figure 4.17 .

FIGURE 4.16 Biosynthesis of Serotonin (5-Hydroxytryptamine, or 5-HT)

Investigators have identified at least nine different types of serotonin receptors: 5-HT1A-1B, 5-HT1D-1F, 5-HT2A-2C, and 5-HT3. Of these the 5-HT1B and 5-HT1D receptors serve as presynaptic autoreceptors. In the dorsal and median raphe nuclei, 5-HT1A receptors serve as autoreceptors in the membrane of dendrites and soma. All 5-HT receptors are metabotropic except for the 5-HT3 receptor, which is ionotropic. The 5-HT3 receptor controls a chloride channel, which means that it produces inhibitory postsynaptic potentials. These receptors appear to play a role in nausea and vomiting, because 5-HT3 antagonists have been found to be useful in treating the side effects of chemotherapy and radiotherapy for the treatment of cancer. Pharmacologists have discovered drugs that serve as agonists or antagonists for some, but not all, of the types of 5-HT receptors.

FIGURE 4.17 Serotonergic Pathways in a Rat Brain

This schematic figure shows the locations of the most important groups of serotonergic neurons and the distribution of their axons and terminal buttons.

(Adapted from Consolazione, A. and Cuello, A. C. CNS serotonin pathways. In Biology of Serotonergic Transmission, edited by N. N. Osborne. Chichester: England: Wiley & Sons, 1982.)

Drugs that inhibit the reuptake of serotonin have found a very important place in the treatment of mental disorders. The best known of these, fluoxetine (Prozac), is used to treat depression, some forms of anxiety disorders, and obsessive-compulsive disorder. These disorders—and their treatment—are discussed in Chapters 16 and 17 . Another drug, fenfluramine , which causes the release of serotonin as well as inhibits its reuptake, was formerly used as an appetite suppressant in the treatment of obesity. Chapter 12 discusses the topic of obesity and its control by means of drugs.

fluoxetine ( floo ox i teen ) A drug that inhibits the reuptake of 5-HT.

fenfluramine ( fen fluor i meen ) A drug that stimulates the release of 5-HT.

Several hallucinogenic drugs produce their effects by interacting with serotonergic transmission. LSD (lysergic acid diethylamide) produces distortions of visual perceptions that some people find awesome and fascinating but that simply frighten other people. This drug, which is effective in extremely small doses, is a direct agonist for postsynaptic 5-HT2A receptors in the forebrain. Another drug, MDMA (methylenedioxymethamphetamine), is both a noradrenergic and a serotonergic agonist and has both excitatory and hallucinogenic effects. Like its relative amphetamine, MDMA (popularly called “ecstasy”) causes noradrenergic transporters to run backwards, thus causing the release of NE and inhibiting its reuptake. This site of action is apparently responsible for the drug’s excitatory effect. MDMA also causes serotonergic transporters to run backwards, and this site of action is apparently responsible for the drug’s hallucinogenic effects. Unfortunately, research indicates that MDMA can damage serotonergic neurons and cause cognitive deficits.

LSD A drug that stimulates 5-HT2A receptors.

MDMA A drug that serves as a noradrenergic and serotonergic agonist, also known as “ecstasy”; has excitatory and hallucinogenic effects.

HISTAMINE

Histamine is produced from histidine—an amino acid—by the action of the enzyme histidine decarboxylase. The cell bodies of histaminergic neurons are found in only one place in the brain: the tuberomammillary nucleus, located in the posterior hypothalamus. Histaminergic neurons send their axons to widespread regions of the cerebral cortex and brain stem. Histamine plays an important role in wakefulness. In fact, the activity of histaminergic neurons is strongly correlated with the states of sleep and wakefulness, and drugs that block histamine receptors cause drowsiness. Histamine also plays a role in control of the digestive system and immune system and is essential for the development of allergic symptoms. Histaminergic H1 receptors are responsible for the itching produced by histamine and for the constriction of the bronchi seen in asthma attacks, H2 receptors stimulate gastric secretions, and both H2and H4 receptors are involved in immune reactions. Cimetidine, an H2 antagonist, blocks gastric acid secretion. H3 receptors serve as autoreceptors on the terminals of histaminergic neurons in the brain; thus, the drug ciproxifan, an H3 antagonist, increases the release of histamine. All types of histamine receptors are found in the central nervous system.

histamine A neurotransmitter that plays an important role in stimulating wakefulness.

The older antihistamines (H1 antagonists) such as diphenhydramine produced drowsiness. In fact, some over-the-counter sleep aids contain these drugs for that very reason. Modern antihistamines that are used to treat the symptoms of allergies do not cross the blood–brain barrier, so they have no direct effects on the brain.

Amino Acids

So far, all of the neurotransmitters I have described are synthesized within neurons: acetylcholine from choline, the catecholamines from the amino acid tyrosine, and serotonin from the amino acid tryptophan. Some neurons secrete simple amino acids as neurotransmitters. Because amino acids are used for protein synthesis by all cells of the brain, it is difficult to prove that a particular amino acid is a neurotransmitter. However, investigators suspect that at least eight amino acids may serve as neurotransmitters in the mammalian central nervous system. As we saw in the introduction to this section, three of them are especially important because they are the most common neurotransmitters in the CNS: glutamate, gamma-aminobutyric acid (GABA), and glycine.

GLUTAMATE

Because glutamate (also called glutamic acid) and GABA are found in very simple organisms, many investigators believe that these neurotransmitters were the first to have evolved. Besides producing postsynaptic potentials by activating postsynaptic receptors, they also have direct excitatory effects (glutamic acid) and inhibitory effects (GABA) on axons; they raise or lower the threshold of excitation, thus affecting the rate at which action potentials occur. These direct effects suggest that these substances had a general modulating role even before the evolutionary development of specific receptor molecules.

glutamate An amino acid; the most important excitatory neurotransmitter in the brain.

Glutamate is the principal excitatory neurotransmitter in the brain and spinal cord. It is produced in abundance by the cells’ metabolic processes. There is no effective way to prevent its synthesis without disrupting other activities of the cell.

Investigators have discovered four major types of glutamate receptors. Three of these receptors are ionotropic and are named after the artificial ligands that stimulate them: the NMDA receptor , the AMPA receptor , and the kainate receptor . The other glutamate receptor—the metabotropic glutamate receptor —is (obviously!) metabotropic. Actually, there appear to be at least eight subtypes of metabotropic glutamate receptors, but little is known about their functions except that some of them serve as presynaptic autoreceptors. The AMPA receptor is the most common glutamate receptor. It controls a sodium channel, so when glutamate attaches to the binding site, it produces EPSPs. The kainate receptor has similar effects.

NMDA receptor A specialized ionotropic glutamate receptor that controls a calcium channel that is normally blocked by Mg2+ ions; has several other binding sites.

AMPA receptor An ionotropic glutamate receptor that controls a sodium channel; stimulated by AMPA.

kainate receptor (kay in ate ) An ionotropic glutamate receptor that controls a sodium channel; stimulated by kainic acid.

metabotropic glutamate receptor ( meh tab a troh pik ) A category of metabotropic receptors that are sensitive to glutamate.

The NMDA receptor has some special—and very important—characteristics. It contains at least six different binding sites: four located on the exterior of the receptor and two located deep within the ion channel. When it is open, the ion channel controlled by the NMDA receptor permits both sodium and calcium ions to enter the cell. The influx of both of these ions causes a depolarization, of course, but the entry of calcium (Ca2+) is especially important. Calcium serves as a second messenger, binding with—and activating—various enzymes within the cell. These enzymes have profound effects on the biochemical and structural properties of the cell. As we shall see, one important result is alteration in the characteristics of the synapse that provide one of the building blocks of a newly formed memory. These effects of NMDA receptors will be discussed in much more detail in Chapter 13 . The drug AP5 (2-amino-5-phosphonopentanoate) blocks the glutamate binding site on the NMDA receptor and impairs synaptic plasticity and certain forms of learning.

AP5 (2-amino-5-phosphonopentanoate) A drug that blocks the glutamate binding site on NMDA receptors.

Figure 4.18 presents a schematic diagram of an NMDA receptor and its binding sites. Obviously, glutamate binds with one of these sites, or we would not call it a glutamate receptor. However, glutamate by itself cannot open the calcium channel. For that to happen, a molecule of glycine must be attached to the glycine binding site, located on the outside of the receptor. (We do not yet understand why glycine—which also serves as an inhibitory neurotransmitter in some parts of the central nervous system—is required for this ion channel to open.) (See Figure 4.18 . )

An additional requirement for the opening of the calcium channel is that a magnesium ion not be attached to the magnesium binding site, located deep within the channel. Under normal conditions, when the postsynaptic membrane is at the resting potential, a magnesium ion (Mg2+) is attracted to the magnesium binding site and blocks the calcium channel. If a molecule of glutamate attaches to its binding site, the channel widens, but the magnesium ion still blocks it, so no calcium can enter the postsynaptic neuron. However, if the postsynaptic membrane is partially depolarized, the magnesium ion is repelled from its binding site. Thus, the NMDA receptor opens only if glutamate is present and the postsynaptic membrane is depolarized. The NMDA receptor, then, is a voltage- and neurotransmitter-dependent ion channel. (See Figure 4.18 . )

FIGURE 4.18 NMDA Receptor

This schematic illustration of an NMDA receptor shows its binding sites.

What about the other three binding sites? If a zinc ion (Zn2+) binds with the zinc binding site, the activity of the NMDA receptor is decreased. On the other hand, the polyamine site has a facilitatory effect. (Polyamines are chemicals that have been shown to be important for tissue growth and development. The significance of the polyamine binding site is not yet understood.) The PCP site, located deep within the ion channel near the magnesium binding site, binds with a hallucinogenic drug, PCP (phencyclidine, also known as “angel dust”). PCP serves as an indirect antagonist; when it attaches to its binding site, calcium ions cannot pass through the ion channel. PCP is a synthetic drug and is not produced by the brain. Thus, it is not the natural ligand of the PCP binding site. What that ligand is and what useful functions it serves are not yet known.

PCP Phencyclidine; a drug that binds with the PCP binding site of the NMDA receptor and serves as an indirect antagonist.

Several drugs affect glutamatergic synapses. As you already know, NMDA, AMPA, and kainate (more precisely, kainic acid) serve as direct agonists at the receptors named after them. In addition, one of the most common drugs—alcohol—serves as an antagonist of NMDA receptors. As we will see in Chapter 18 , this effect is responsible for the seizures that can be provoked by sudden withdrawal from heavy long-term alcohol intake.

GABA

GABA (gamma-aminobutyric acid) is produced from glutamic acid by the action of an enzyme (glutamic acid decarboxylase, or GAD) that removes a carboxyl group. The drug allylglycine inactivates GAD and thus prevents the synthesis of GABA (step 2 of Figure 4.4 ). GABA is an inhibitory neurotransmitter, and it appears to have a widespread distribution throughout the brain and spinal cord. Two GABA receptors have been identified: GABAA and GABAB. The GABAA receptor is ionotropic and controls a chloride channel; the GABAB receptor is metabotropic and controls a potassium channel.

GABA An amino acid; the most important inhibitory neurotransmitter in the brain.

allylglycine A drug that inhibits the activity of GAD and thus blocks the synthesis of GABA.

As you know, neurons in the brain are greatly interconnected. Without the activity of inhibitory synapses these interconnections would make the brain unstable. That is, through excitatory synapses neurons would excite their neighbors, which would then excite their neighbors, which would then excite the originally active neurons, and so on, until most of the neurons in the brain would be firing uncontrollably. In fact, this event does sometimes occur, and we refer to it as a seizure. (Epilepsy is a neurological disorder characterized by the presence of seizures.) Normally, an inhibitory influence is supplied by GABA-secreting neurons, which are present in large numbers in the brain. Some investigators believe that one of the causes of epilepsy is an abnormality in the biochemistry of GABA-secreting neurons or in GABA receptors.

Like NMDA receptors, GABAA receptors are complex; they contain at least five different binding sites. The primary binding site is, of course, for GABA. The drug muscimol (derived from the ACh agonist muscarine) serves as a direct agonist for this site (step 6 of Figure 4.4 ). Another drug, bicuculline , blocks this GABA binding site, serving as a direct antagonist (step 7 of Figure 4.4 ). A second site on the GABAAreceptor binds with a class of tranquilizing drugs called the benzodiazepines . These drugs include diazepam (Valium) and chlordiazepoxide (Librium), which are used to reduce anxiety, promote sleep, reduce seizure activity, and produce muscle relaxation. The third site binds with barbiturates. The fourth site binds with various steroids, including some steroids used to produce general anesthesia. The fifth site binds with picrotoxin, a poison found in an East Indian shrub. In addition, alcohol binds with an as-yet unknown site on the GABAA receptor. (See Figure 4.19 . )

muscimol (musk i mawl ) A direct agonist for the GABA binding site on the GABAA receptor.

bicuculline ( by kew kew leen ) A direct antagonist for the GABA binding site on the GABAA receptor.

benzodiazepine ( ben zoe dy azz a peen ) A category of anxiolytic drugs; an indirect agonist for the GABAA receptor.

FIGURE 4.19 GABAA Receptor

This schematic illustration of a GABAA receptor shows its binding sites.

Barbiturates, drugs that bind to the steroid site, and benzodiazepines all promote the activity of the GABAA receptor; thus, all these drugs serve as indirect agonists. The benzodiazepines are very effective anxiolytics , or “anxiety-dissolving” drugs. They are often used to treat people with anxiety disorders. In addition, some benzodiazepines serve as effective sleep medications, and others are used to treat some types of seizure disorder.

anxiolytic ( angz ee oh lit ik ) An anxiety-reducing effect.

Picrotoxin has effects opposite to those of benzodiazepines and barbiturates: It inhibits the activity of the GABAA receptor, thus serving as an indirect antagonist. In high enough doses, this drug causes convulsions.

Various steroid hormones are normally produced in the body, and some hormones related to progesterone (the principal pregnancy hormone) act on the steroid binding site of the GABAA receptor, producing a relaxing, anxiolytic sedative effect. However, the brain does not produce Valium, barbiturates, or picrotoxin. The natural ligands for these binding sites have not yet been discovered.

What about the GABAB receptor? This metabotropic receptor, coupled to a G protein, serves as both a postsynaptic receptor and a presynaptic autoreceptor. A GABAB agonist, baclofen, serves as a muscle relaxant. Another drug, CGP 335348, serves as an antagonist. The activation of GABAB receptors opens potassium channels, producing hyperpolarizing inhibitory postsynaptic potentials.

GLYCINE

The amino acid glycine appears to be the inhibitory neurotransmitter in the spinal cord and lower portions of the brain. Little is known about its biosynthetic pathway; there are several possible routes, but not enough is known to decide how neurons produce glycine. The bacteria that cause tetanus (lockjaw) release a chemical that prevents the release of glycine (and GABA as well); the removal of the inhibitory effect of these synapses causes muscles to contract continuously.

glycine (gly seen ) An amino acid; an important inhibitory neurotransmitter in the lower brain stem and spinal cord.

The glycine receptor is ionotropic, and it controls a chloride channel. Thus, when it is active, it produces inhibitory postsynaptic potentials. The drug strychnine , an alkaloid found in the seeds of the Strychnos nux vomica, a tree found in India, serves as a glycine antagonist. Strychnine is very toxic, and even relatively small doses cause convulsions and death. No drugs have yet been found that serve as specific glycine agonists.

strychnine (strik neen) A direct antagonist for the glycine receptor.

Researchers have discovered that some terminal buttons in the brain release both glycine and GABA (Jonas, Bischofberger, and Sandkühler, 1998 ; Nicoll and Malenka, 1998 ). The apparent advantage for the corelease of these two inhibitory neurotransmitters is the production of rapid, long-lasting postsynaptic potentials: The glycine stimulates rapid ionotropic receptors, and the GABA stimulates long-lasting metabotropic receptors. Obviously, the postsynaptic membrane at these synapses contains both glycine and GABA receptors.

Peptides

Recent studies have discovered that the neurons of the central nervous system release a large variety of peptides. Peptides consist of two or more amino acids linked together by peptide bonds. All the peptides that have been studied so far are produced from precursor molecules. These precursors are large polypeptides that are broken into pieces by special enzymes. Neurons manufacture both the polypeptides and the enzymes needed to break them apart in the right places. The appropriate sections of the polypeptides are retained, and the rest are destroyed. Because the synthesis of peptides takes place in the soma, vesicles containing these chemicals must be delivered to the terminal buttons by axoplasmic transport.

Peptides are released from all parts of the terminal button, not just from the active zone; thus, only a portion of the molecules are released into the synaptic cleft. The rest presumably act on receptors belonging to other cells in the vicinity. Once released, peptides are destroyed by enzymes. There is no mechanism for reup-take and recycling of peptides.

Several different peptides are released by neurons. Although most peptides appear to serve as neuromodulators, some act as neurotransmitters. One of the best known families of peptides is the endogenous opioids . (Endogenous means “produced from within”; opioid means “like opium.”) Research has revealed that opiates (drugs such as opium, morphine, and heroin) reduce pain because they have direct effects on the brain. (Please note that the term opioid refers to endogenous chemicals, and opiaterefers to drugs.) Pert, Snowman, and Snyder ( 1974 ) discovered that neurons in a localized region of the brain contain specialized receptors that respond to opiates. Then, soon after the discovery of the opiate receptor, other neuroscientists discovered the natural ligands for these receptors (Hughes et al., 1975 ; Terenius and Wahlström, 1975 ), which they called enkephalins (from the Greek word enkephalos, “in the head”). We now know that the enkephalins are only two members of a family of endogenous opioids, all of which are synthesized from one of three large peptides that serve as precursors. In addition, we know that there are at least three different types of opiate receptors: μ (mu), δ (delta), and κ (kappa).

endogenous opioid ( en dodge en us oh pee oyd ) A class of peptides secreted by the brain that act as opiates.

enkephalin ( en keff a lin ) One of the endogenous opioids.

Several different neural systems are activated when opiate receptors are stimulated. One type produces analgesia, another inhibits species-typical defensive responses such as fleeing and hiding, and another stimulates a system of neurons involved in reinforcement (“reward”). The last effect explains why opiates are often abused. The situations that cause neurons to secrete endogenous opioids are discussed in Chapter 7 , and the brain mechanisms of opiate addiction are discussed in Chapter 18 .

So far, pharmacologists have developed only two types of drugs that affect neural communication by means of opioids: direct agonists and antagonists. Many synthetic opiates, including heroin (dihydromorphine), have been developed, and some are used clinically as analgesics (step 6 of Figure 4.4 ). Several opiate receptor blockers have also been developed (step 7 of Figure 4.4 ). One of them, naloxone , is used clinically to reverse opiate intoxication. This drug has saved the lives of many drug abusers who would otherwise have died of an overdose of heroin.

naloxone ( na lox own ) A drug that blocks opiate receptors.

As we saw in Chapter 2 , many terminal buttons contain two different types of synaptic vesicles, each filled with a different substance. These terminal buttons release peptides in conjunction with a “classical” neurotransmitter (one of those I just described). One reason for the corelease of peptides is their ability to regulate the sensitivity of presynaptic or postsynaptic receptors to the neurotransmitter. For example, the terminal buttons of the salivary nerve of the cat (which control the secretion of saliva) release both acetylcholine and a peptide called VIP. When the axons fire at a low rate, only ACh is released and only a little saliva is secreted. At a higher rate, both ACh and VIP are secreted, and the VIP dramatically increases the sensitivity of the muscarinic receptors in the salivary gland to ACh; thus, much saliva is released.

Several peptide hormones released by endocrine glands are also found in the brain, where they serve as neuromodulators. In some cases the peripheral and central peptides perform related functions. For example, outside the nervous system the hormone angiotensin acts directly on the kidneys and blood vessels to produce effects that help the body cope with the loss of fluid, and inside the nervous system circuits of neurons that use angiotensin as a neurotransmitter perform complementary functions, including the activation of neural circuits that produce thirst. The existence of the blood–brain barrier keeps hormones in the general circulation separate from the extracellular fluid in the brain, which means that the same peptide molecule can have different effects in these two regions.

Many peptides produced in the brain have interesting behavioral effects, which will be discussed in subsequent chapters.

Lipids

Various substances derived from lipids can serve to transmit messages within or between cells. The best known, and probably the most important, are the endocannabinoids (“endogenous cannabis-like substances”)—natural ligands for the receptors that are responsible for the physiological effects of the active ingredient in marijuana. Matsuda et al. ( 1990 ) discovered that THC (tetrahydrocannabinol, the active ingredient of marijuana) stimulates cannabinoid receptors located in specific regions of the brain. (See Figure 4.20 . ) Two types of cannabinoid receptors, CB1 and CB2, both metabotropic, have since been discovered. CB1 receptors are found in the brain, especially in the frontal cortex, anterior cingulate cortex, basal ganglia, cerebellum, hypothalamus, and hippocampus. Very low levels of CB1 receptors are found in the brain stem, which accounts for the low toxicity of THC. CB2 receptors are found outside the brain, especially in cells of the immune system.

endocannabinoid ( en do can ab in oyd ) A lipid; an endogenous ligand for cannabinoid receptors, which also bind with THC, the active ingredient of marijuana.

THC The active ingredient in marijuana; activates CB1 receptors in the brain.

THC produces analgesia and sedation, stimulates appetite, reduces nausea caused by drugs used to treat cancer, relieves asthma attacks, decreases pressure within the eyes in patients with glaucoma, and reduces the symptoms of certain motor disorders. On the other hand, THC interferes with concentration and memory, alters visual and auditory perception, and distorts perceptions of the passage of time. Devane et al. ( 1992 ) discovered the first natural ligand for the THC receptor: a lipidlike substance that they named anandamide , from the Sanskrit word ananda, or “bliss.” A few years after the discovery of anandamide, Mechoulam et al. ( 1995 ) discovered another endocannabinoid, 2-arachidonyl glycerol (2-AG).

FIGURE 4.20 Cannabinoid Receptors in a Rat Brain

In this autoradiogram the brain has been incubated in a solution containing a radioactive ligand for cannabinoid receptors. The receptors are indicated by dark areas. (Autoradiography is described in Chapter 5 .) (Br St = brain stem, Cer = cerebellum, CP = caudate nucleus/putamen, Cx = cortex, EP = entopeduncular nucleus, GP = globus pallidus, Hipp = hippocampus, SNr = substantia nigra.)

(Courtesy of Miles Herkenham, National Institute of Mental Health, Bethesda, MD.)

anandamide ( a nan da mide ) The first cannabinoid to be discovered and probably the most important one.

Anandamide seems to be synthesized on demand; that is, it is produced and released as it is needed and is not stored in synaptic vesicles. It is deactivated by an enzyme, FAAH (fatty acid amide hydrolase), which is present in anandamide-secreting neurons. Because the enzyme is found there, molecules of anandamide must be transported back into these neurons, which is accomplished by anandamide transporters. Besides THC, several drugs have been discovered that affect the actions of the endocannabinoids. CB1 receptors are blocked by the drug rimonabant , the enzyme FAAH is inhibited by MAFP , and reuptake is inhibited by AM1172 .

FAAH Fatty acid amide hydrolase, the enzyme that destroys anandamide after it is brought back into the cell by anandamide transporters.

rimonabant A drug that blocks CB1 receptors.

MAFP A drug that inhibits FAAH; prevents the breakdown of anandamide.

AM1172 A drug that inhibits the reuptake of anandamide.

CB1 receptors are found on terminal buttons of glutamatergic, GABAergic, acetylcholinergic, noradrenergic, dopaminergic, and serotonergic neurons, where they serve as presynaptic heteroreceptors, regulating neurotransmitter release (Iversen, 2003 ). When activated, the receptors open potassium channels in the terminal buttons, shortening the duration of action potentials there and decreasing the amount of neurotransmitter that is released. When neurons release cannabinoids, the chemicals diffuse a distance of approximately 20 μm in all directions, and their effects persist for several tens of seconds. The short-term memory impairment that accompanies marijuana use appears to be caused by the action of THC on CB1 receptors in the hippocampus. Endocannabinoids also appear to play an essential role in the reinforcing effects of opiates: A targeted mutation that prevents the production of CB1 receptors abolishes the reinforcing effects of morphine but not of cocaine, amphetamine, or nicotine (Cossu et al., 2001 ). These effects of cannabinoids are discussed further in Chapter 18 .

I mentioned three paragraphs ago that THC (and, of course, the endocannabinoids) have an analgesic effect. Agarwal et al. ( 2007 ) found that THC exerts its analgesic effects by stimulating CB1 receptors in the peripheral nervous system. In addition, a commonly used over-the-counter analgesic, acetaminophen(known as paracetamol in many countries), also acts on these receptors. Once it enters the blood, acetaminophen is converted into another compound that then joins with arachidonic acid, the precursor of anandamide. This compound binds with peripheral CB1 receptors and activates them, reducing pain sensation. Because the compound does not cross the blood–brain barrier, it does not produce effects like those of THC. Administration of a CB1 antagonist completely blocks the analgesic effect of acetaminophen (Bertolini et al., 2006 ).

Nucleosides

A nucleoside is a compound that consists of a sugar molecule bound with a purine or pyrimidine base. One of these compounds, adenosine (a combination of ribose and adenine), serves as a neuromodulator in the brain.

adenosine ( a den oh seen ) A nucleoside; a combination of ribose and adenine; serves as a neuromodulator in the brain.

Adenosine is known to be released by astrocytes when neurons in the brain are short of fuel or oxygen. The release of adenosine activates receptors on nearby blood vessels and causes them to dilate, increasing the flow of blood and helping to bring more of the needed substances to the region. Adenosine also acts as a neuromodulator, through its action on at least three different types of adenosine receptors. Adenosine receptors are coupled to G proteins, and their effect is to open potassium channels, producing inhibitory postsynaptic potentials.

TABLE 4.2 Typical Caffeine Content of Chocolate and Several Beverages

Item	Caffeine Content
Chocolates
Baking chocolate	35 mg/oz
Milk chocolate	6 mg/oz
Beverages
Coffee	85 mg/5-oz cup
Decaffeinated coffee	3 mg/5-oz cup
Tea (brewed 3 minutes)	28 mg/5-oz cup
Cocoa or hot chocolate	30 mg/5-oz cup
Cola drink	30–46 mg/12-oz container

Based on data from Somani and Gupta, 1988.

Because adenosine receptors suppress neural activity, adenosine and other adenosine receptor agonists have generally inhibitory effects on behavior. In fact, as we will see in Chapter 9 , there is good evidence that adenosine receptors play an important role in the control of sleep. For example, the amount of adenosine in the brain increases during wakefulness and decreases during sleep. In fact, the accumulation of adenosine after prolonged wakefulness may be the most important cause of the sleepiness that ensues. A very common drug, caffeine , blocks adenosine receptors (step 7 of Figure 4.4 ) and hence produces excitatory effects. Caffeine is a bitter-tasting alkaloid found in coffee, tea, cocoa beans, and other plants. In much of the world a majority of the adult population ingests caffeine every day—fortunately, without apparent harm. (See Table 4.2 . )

caffeine A drug that blocks adenosine receptors.

Soluble Gases

Recently, investigators have discovered that neurons use at least two simple, soluble gases—nitric oxide and carbon monoxide—to communicate with one another. One of these, nitric oxide (NO) , has received the most attention. Nitric oxide (not to be confused with nitrous oxide, or laughing gas) is a soluble gas that is produced by the activity of an enzyme found in certain neurons. Researchers have found that NO is used as a messenger in many parts of the body; for example, it is involved in the control of the muscles in the wall of the intestines, it dilates blood vessels in regions of the brain that become metabolically active, and it stimulates the changes in blood vessels that produce penile erections (Culotta and Koshland, 1992 ). As we will see in Chapter 13 , NO may also play a role in the establishment of neural changes that are produced by learning.

nitric oxide (NO) A gas produced by cells in the nervous system; used as a means of communication between cells.

All of the neurotransmitters and neuromodulators discussed so far (with the exception of anandamide and adenosine) are stored in synaptic vesicles and released by terminal buttons. Nitric oxide is produced in several regions of a nerve cell—including dendrites—and is released as soon as it is produced. More accurately, it diffuses out of the cell as soon as it is produced. It does not activate membrane-bound receptors but enters neighboring cells, where it activates an enzyme responsible for the production of a second messenger, cyclic GMP. Within a few seconds of being produced, nitric oxide is converted into biologically inactive compounds.

Nitric oxide is produced from arginine, an amino acid, by the activation of an enzyme known as nitric oxide synthase . This enzyme can be inactivated (step 2 of Figure 4.4 ) by a drug called L-NAME (nitro-L-arginine methyl ester).

nitric oxide synthase The enzyme responsible for the production of nitric oxide.

You have undoubtedly heard of a drug called sildenafil (more commonly known as Viagra), which is used to treat men who have erectile dysfunction—difficulty maintaining a penile erection. As we just saw, nitric oxide produces its physiological effects by stimulating the production of cyclic GMP. Although nitric oxide lasts only for a few seconds, cyclic GMP lasts somewhat longer but is ultimately destroyed by an enzyme. Molecules of sildenafil bind with this enzyme and thus cause cyclic GMP to be destroyed at a much slower rate. As a consequence, an erection is maintained for a longer time. (By the way, sildenafil has effects on other parts of the body and is used to treat altitude sickness and other vascular disorders.)

SECTION SUMMARY: Neurotransmitters and Neuromodulators

The nervous system contains a variety of neurotransmitters, each of which interacts with one or more specialized receptors. The neurotransmitters that have received the most study are acetylcholine and the monoamines: dopamine, norepinephrine, 5-hydroxytryptamine (serotonin), and histamine. The synthesis of these neurotransmitters is controlled by a series of enzymes. Several amino acids also serve as neurotransmitters, the most important of which are glutamate (glutamic acid), GABA, and glycine. Glutamate serves as an excitatory neurotransmitter; the others serve as inhibitory neurotransmitters.

Peptide neurotransmitters consist of chains of amino acids. Like proteins, peptides are synthesized at the ribosomes according to sequences coded for by the chromosomes. The best-known class of peptides in the nervous system includes the endogenous opioids, whose effects are mimicked by drugs such as opium and heroin. Two lipids serve as chemical messengers: Anandamide and 2-AG are endogenous ligands for cannabinoid receptors. CB1 receptors are found in the central nervous system, and CB2 receptors are found outside the blood–brain barrier. Adenosine, a nucleoside that has inhibitory effects on synaptic transmission, is released by neurons and glial cells in the brain. In addition, two soluble gases—nitric oxide and carbon monoxide—can diffuse out of the cell in which they are produced and trigger the production of a second messenger in adjacent cells.

This chapter has mentioned many drugs and their effects. They are summarized for your convenience in Table 4.3 .

■ THOUGHT QUESTIONS

What type(s) of drug might potentially be used to treat seizure disorders? Explain.

One of the causes of the symptoms of schizophrenia may be excessive activity at dopaminergic synapses in the brain. Explain why drug treatment of Parkinson’s disease can sometimes provoke these symptoms.

TABLE 4.3 Drugs Mentioned in This Chapter

Neurotransmitter

Name of Drug

Effect of Drug

Effect on Synaptic Transmission

Acetylcholine (ACh)

Botulinum toxin

Black widow spider venom

Nicotine

Curare

Muscarine

Atropine

Neostigmine

Hemicholinium

Blocks release of ACh

Stimulates release of ACh

Stimulates nicotinic receptors

Blocks nicotinic receptors

Stimulates muscarinic receptors

Blocks muscarinic receptors

Inhibits acetylcholinesterase

Inhibits reuptake of choline

Antagonist

Agonist

Antagonist

Agonist

Antagonist

Agonist

Antagonist

Dopamine (DA)

L-DOPA

AMPT

Reserpine

Chlorpromazine

Clozapine

Cocaine, methylphenidate

Amphetamine

Deprenyl

Facilitates synthesis of DA

Inhibits synthesis of DA

Inhibits storage of DA in synaptic vesicles

Blocks D2 receptors

Blocks D4 receptors

Blocks DA reuptake

Stimulates release of DA

Blocks MAO-B

Agonist

Antagonist

Agonist

Norepinephrine (NE)

Fusaric acid

Reserpine

Idazoxan

Desipramine

Moclobemide

MDMA, amphetamine

Inhibits synthesis of NE

Inhibits storage of NE in synaptic vesicles

Blocks α2 autoreceptors

Inhibits reuptake of NE

Inhibits MAO-A

Stimulates release of NE

Antagonist

Agonist

Serotonin (5-HT)

PCPA

Reserpine

Fenfluramine

Fluoxetine

LSD

MDMA

Inhibits synthesis of 5-HT

Inhibits storage of 5-HT in synaptic vesicles

Stimulates release of 5-HT

Inhibits reuptake of 5-HT

Stimulates 5-HT2A receptors

Stimulates release of 5-HT

Antagonist

Agonist

Histamine

Diphenhydramine

Cimetidine

Ciproxifan

Blocks H1 receptors

Blocks H2 receptors

Blocks H3 autoreceptors

Antagonist

Agonist

Glutamate

AMPA

Kainic acid

NMDA

AP5

Stimulates AMPA receptor

Stimulates kainate receptor

Stimulates NMDA receptor

Blocks NMDA receptor

Agonist

Antagonist

GABA

Allylglycine

Muscimol

Bicuculline

Benzodiazepines

Inhibits synthesis of GABA

Stimulates GABA receptors

Blocks GABA receptors

Serve as indirect GABA agonist

Antagonist

Agonist

Antagonist

Agonist

Glycine

Strychnine

Blocks glycine receptors

Antagonist

Opioids

Opiates (morphine, heroin, etc.)

Naloxone

Stimulates opiate receptors

Blocks opiate receptors

Agonist

Antagonist

Anandamide

Rimonabant

THC

MAFP

AM1172

Blocks cannabinoid CB1 receptors

Stimulates cannabinoid CB1 receptors

Inhibits FAAH

Blocks reuptake of anandamide

Antagonist

Agonist

Adenosine

Caffeine

Blocks adenosine receptors

Antagonist

Nitric oxide (NO)

L-NAME

Sildenafil

Inhibits synthesis of NO

Inhibits destruction of cyclic GMP

Antagonist

Agonist

Review Questions

Study and Review on MyPsychLab

Describe the routes of administration and the distribution of drugs within the body.

Describe drug effectiveness, the effects of repeated administration, and the placebo effect.

Describe the effects of drugs on neurotransmitters and presynaptic and postsynaptic receptors.

Review the general role of neurotransmitters and neuromodulators and describe the acetylcholinergic pathways in the brain and the drugs that affect these neurons.

Describe the monoaminergic pathways in the brain and the drugs that affect these neurons.

Review the role of neurons that release amino acid neurotransmitters and describe drugs that affect these neurons.

Describe the effects of peptides, lipids, nucleosides, and soluble gases released by neurons.

Explore the Virtual Brain in MyPsychLab

■ DRUG ADDICTION AND BRAIN REWARD CIRCUITS

Many of the drugs described in this chapter have the potential for abuse. The abuse potential appears to be related to activation of the brain reward circuits. Indeed, every drug of abuse, with one known exception, ultimately triggers the release of dopamine in the brain reward circuitry. The Drug Addiction and Brain Reward Circuits module of the virtual brain show these circuits.

Now transition to the "Classical World" or the world of the Greco-Roman civilizations, here is the discussion topic relating to these societies, which has multiple parts:

First, identify the structures of society and of government in Classical Athens (590-404 BC), Classical Sparta (ca. 650-ca. 370 BC), Classical Persia (559-330 BC), and the Classical Hellenistic Empire (330-ca.134 BC); then, second, discuss the distinctions between the Classical Athenian, Spartan, Persian, and Hellenistic forms of government and society; then, third, assess which you feel was most effective and why/by what definition of "effective". Then, once you've considered all these Classical societies, please identify the structures of society and of government in the Roman Republic (509-31 BC) and the Roman Empire (31 BC-ca. 476 AD), differentiating between different eras in the Republic and Empire as you see fit; then compare the Roman Republic and Roman Empire to Classical Athens and Sparta and, again, assess which you feel was most effective and why/by what definition of "effective"; then, finally, evaluate which of these Classical World societies you feel has had the greatest impact on our modern 21st Century American government and society and why. Feel free to relate these societies to our contemporary society and current events - especially given the 2016 election and its results - but make sure to focus on the historical context, philosophies, and events of the Classical World in your discussions.

Modules chapter 2

chapter 2 Structure and Functions of Cells of the Nervous System

Outline

· ■ Cells of the Nervous System

Neurons

Supporting Cells

The Blood–Brain Barrier

Section Summary

· ■ Communication Within a Neuron

Neural Communication: An Overview

Measuring Electrical Potentials of Axons

The Membrane Potential: Balance of Two Forces

The Action Potential

Conduction of the Action Potential

Section Summary

· ■ Communication Between Neurons

Structure of Synapses

Release of Neurotransmitter

Activation of Receptors

Postsynaptic Potentials

Termination of Postsynaptic Potentials

Effects of Postsynaptic Potentials: Neural Integration

Autoreceptors

Other Types of Synapses

Nonsynaptic Chemical Communication

Section Summary

Kathryn D. was getting desperate. All her life she had been healthy and active, eating wisely and keeping fit with sports and regular exercise. She went to her health club almost every day for a session of low-impact aerobics followed by a swim. But several months ago she began having trouble keeping up with her usual schedule. At first, she found herself getting tired toward the end of her aerobics class. Her arms, particularly, seemed to get heavy. Then when she entered the pool and started swimming, she found that it was hard to lift her arms over her head; she abandoned the crawl and the backstroke and did the sidestroke and breaststroke instead. She did not have any flulike symptoms, so she told herself that she needed more sleep and perhaps she should eat a little more.

Over the next few weeks, however, things only got worse. Aerobics classes were becoming an ordeal. Her instructor became concerned and suggested that Kathryn see her doctor. She did so, but he could find nothing wrong with her. She was not anemic, showed no signs of an infection, and seemed to be well nourished. He asked how things were going at work.

“Well, lately I’ve been under some pressure,” she said. “The head of my department quit a few weeks ago, and I’ve taken over his job temporarily. I think I have a chance of getting the job permanently, but I feel as if my bosses are watching me to see whether I’m good enough for the job.” Kathryn and her physician agreed that increased stress could be the cause of her problem. “I’d prefer not to give you any medication at this time,” he said, “but if you don’t feel better soon we’ll have a closer look at you.”

She did feel better for a while, but then all of a sudden her symptoms got worse. She quit going to the health club and found that she even had difficulty finishing a day’s work. She was certain that people were noticing that she was no longer her lively self, and she was afraid that her chances for the promotion were slipping away. One afternoon she tried to look up at the clock on the wall and realized that she could hardly see—her eyelids were drooping, and her head felt as if it weighed a hundred pounds. Just then, one of her supervisors came over to her desk, sat down, and asked her to fill him in on the progress she had been making on a new project. As she talked, she found herself getting weaker and weaker. Her jaw was getting tired, even her tongue was getting tired, and her voice was getting weaker. With a sudden feeling of fright she realized that the act of breathing seemed to take a lot of effort. She managed to finish the interview, but immediately afterward she packed up her briefcase and left for home, saying that she had a bad headache.

She telephoned her physician, who immediately arranged for her to go to the hospital to be seen by Dr. T., a neurologist. Dr. T. listened to a description of Kathryn’s symptoms and examined her briefly. She said to Kathryn, “I think I know what may be causing your symptoms. I’d like to give you an injection and watch your reaction.” She gave some orders to the nurse, who left the room and came back with a syringe. Dr. T. took it, swabbed Kathryn’s arm, and injected the drug. She started questioning Kathryn about her job. Kathryn answered slowly, her voice almost a whisper. As the questions continued, she realized that it was getting easier and easier to talk. She straightened her back and took a deep breath. Yes, she was sure. Her strength was returning! She stood up and raised her arms above her head. “Look,” she said, her excitement growing. “I can do this again. I’ve got my strength back! What was that you gave me? Am I cured?”

(For an answer to her question, see p. 59 .)

All we can do—perceive, think, learn, remember, act—is made possible by the integrated activity of the cells of the nervous system. This chapter describes the structure and functions of these cells. Information, in the form of light, sound waves, odors, tastes, or contact with objects, is gathered from the environment by specialized cells called sensory neurons . Movements are accomplished by the contraction of muscles, which are controlled by motor neurons . (The term motor is used here in its original sense to refer to movement, not to a mechanical engine.) And in between sensory neurons and motor neurons come the interneurons —neurons that lie entirely within the central nervous system. Local interneurons form circuits with nearby neurons and analyze small pieces of information. Relay interneurons connect circuits of local interneurons in one region of the brain with those in other regions. Through these connections, circuits of neurons throughout the brain perform functions essential to tasks such as perceiving, learning, remembering, deciding, and controlling complex behaviors. How many neurons are there in the human nervous system? The most common estimate is around 100 billion, but no one has counted them yet.

sensory neuron A neuron that detects changes in the external or internal environment and sends information about these changes to the central nervous system.

motor neuron A neuron located within the central nervous system that controls the contraction of a muscle or the secretion of a gland.

interneuron A neuron located entirely within the central nervous system.

To understand how the nervous system controls behavior, we must first understand its parts—the cells that compose it. Because this chapter deals with cells, you need not be familiar with the structure of the nervous system, which is presented in Chapter 3 . However, you need to know that the nervous system consists of two basic divisions: the central nervous system and the peripheral nervous system. The central nervous system (CNS) consists of the parts that are encased by the bones of the skull and spinal column: the brain and the spinal cord. The peripheral nervous system (PNS) is found outside these bones and consists of the nerves and most of the sensory organs.

central nervous system (CNS) The brain and spinal cord.

peripheral nervous system (PNS) The part of the nervous system outside the brain and spinal cord, including the nerves attached to the brain and spinal cord.

Cells of the Nervous System

The first part of this chapter is devoted to a description of the most important cells of the nervous system—neurons and their supporting cells—and to the blood–brain barrier, which provides neurons in the central nervous system with chemical isolation from the rest of the body.

Neurons

BASIC STRUCTURE

The neuron (nerve cell) is the information-processing and information-transmitting element of the nervous system. Neurons come in many shapes and varieties, according to the specialized jobs they perform. Most neurons have, in one form or another, the following four structures or regions: (1) cell body, or soma; (2) dendrites; (3) axon; and (4) terminal buttons. To see an interactive animation of the information presented in the following section, Simulate neurons and supporting cells, on MyPsychLab.

Soma.

The soma (cell body) contains the nucleus and much of the machinery that provides for the life processes of the cell. (See Figure 2.1 . ) Its shape varies considerably in different kinds of neurons.

soma The cell body of a neuron, which contains the nucleus.

Dendrites.

FIGURE 2.1 The Principal Parts of a Multipolar Neuron

Dendron is the Greek word for tree, and the dendrites of the neuron look very much like trees. (Look again at Figure 2.1 .) Neurons “converse” with one another, and dendrites serve as important recipients of these messages. The messages that pass from neuron to neuron are transmitted across the synapse , a junction between the terminal buttons (described later) of the sending cell and a portion of the somatic or dendritic membrane of the receiving cell. (The word synapse derives from the Greek sunaptein, “to join together.”) Communication at a synapse proceeds in one direction: from the terminal button to the membrane of the other cell. (Like many general rules, this one has some exceptions. As we will see in Chapter 4 , some synapses pass information in both directions.)

dendrite A branched, treelike structure attached to the soma of a neuron; receives information from the terminal buttons of other neurons.

synapse A junction between the terminal button of an axon and the membrane of another neuron.

Axon.

The axon is a long, slender tube, often covered by a myelin sheath. (The myelin sheath is described later.) The axon carries information from the cell body to the terminal buttons. (Look again at Figure 2.1 .) The basic message it carries is called an action potential. This function is an important one and will be described in more detail later in the chapter. For now, it suffices to say that an action potential is a brief electrical/chemical event that starts at the end of the axon next to the cell body and travels toward the terminal buttons. The action potential is like a brief pulse; in any given axon the action potential is always of the same size and duration. When it reaches a point where the axon branches, it splits but does not diminish in size. Each branch receives a full-strength action potential.

axon The long, thin, cylindrical structure that conveys information from the soma of a neuron to its terminal buttons.

Like dendrites, axons and their branches come in different shapes. In fact, the three principal types of neurons are classified according to the way in which their axons and dendrites leave the soma. The neuron depicted in Figure 2.1 is the most common type found in the central nervous system; it is a multipolar neuron . In this type of neuron the somatic membrane gives rise to one axon but to the trunks of many dendritic trees. Bipolar neurons give rise to one axon and one dendritic tree, at opposite ends of the soma. (See Figure 2.2a . ) Bipolar neurons are usually sensory; that is, their dendrites detect events occurring in the environment and communicate information about these events to the central nervous system.

multipolar neuron A neuron with one axon and many dendrites attached to its soma.

bipolar neuron A neuron with one axon and one dendrite attached to its soma.

The third type of nerve cell is the unipolar neuron . It has only one stalk, which leaves the soma and divides into two branches a short distance away. (See Figure 2.2b . )

unipolar neuron A neuron with one axon attached to its soma; the axon divides, with one branch receiving sensory information and the other sending the information into the central nervous system.

Unipolar neurons, like bipolar neurons, transmit sensory information from the environment to the CNS. The arborizations (treelike branches) outside the CNS are dendrites; the arborizations within the CNS end in terminal buttons. The dendrites of most unipolar neurons detect touch, temperature changes, and other sensory events that affect the skin. Other unipolar neurons detect events in our joints, muscles, and internal organs.

The central nervous system communicates with the rest of the body through nerves attached to the brain and to the spinal cord. Nerves are bundles of many thousands of individual fibers, all wrapped in a tough, protective membrane. Under a microscope, nerves look something like telephone cables, with their bundles of wires. (See Figure 2.3 . ) Like the individual wires in a telephone cable, nerve fibers transmit messages through the nerve, from a sense organ to the brain or from the brain to a muscle or gland.

FIGURE 2.2 Neurons

Pictured here are (a) a bipolar neuron, primarily found in sensory systems (for example, vision and audition), and (b) a unipolar neuron, found in the somatosensory system (touch, pain, and the like).

Terminal Buttons.

Most axons divide and branch many times. At the ends of the twigs are found little knobs called terminal buttons . (Some neuroscientists prefer the original French word bouton, and others simply refer to them as terminals.) Terminal buttons have a very special function: When an action potential traveling down the axon reaches them, they secrete a chemical called a neurotransmitter . This chemical (there are many different ones in the CNS) either excites or inhibits the receiving cell and thus helps to determine whether an action potential occurs in its axon. Details of this process will be described later in this chapter.

terminal button The bud at the end of a branch of an axon; forms synapses with another neuron; sends information to that neuron.

neurotransmitter A chemical that is released by a terminal button; has an excitatory or inhibitory effect on another neuron.

An individual neuron receives information from the terminal buttons of axons of other neurons—and the terminal buttons of its axons form synapses with other neurons. A neuron may receive information from dozens or even hundreds of other neurons, each of which can form a large number of synaptic connections with it. Figure 2.4 illustrates the nature of these connections. As you can see, terminal buttons can form synapses on the membrane of the dendrites or the soma. (See Figure 2.4 . )

INTERNAL STRUCTURE

FIGURE 2.3 Nerves

A nerve consists of a sheath of tissue that encases a bundle of individual nerve fibers (also known as axons). BV = blood vessel; A = individual axons.

(From Tissues and Organs: A Text-Atlas of Scanning Electron Microscopy, by Richard G. Kessel and Randy H. Kardon. Copyright © 1979 by W. H. Freeman and Co. Reprinted by permission of Barbara Kessel and Randy Kardon.)

Figure 2.5 illustrates the internal structure of a typical multipolar neuron. (See Figure 2.5 . ) The membrane defines the boundary of the cell. It consists of a double layer of lipid (fatlike) molecules. Embedded in the membrane are a variety of protein molecules that have special functions. Some proteins detect substances outside the cell (such as hormones) and pass information about the presence of these substances to the interior of the cell. Other proteins control access to the interior of the cell, permitting some substances to enter but barring others. Still other proteins act as transporters, actively carrying certain molecules into or out of the cell. Because the proteins that are found in the membrane of the neuron are especially important in the transmission of information, their characteristics will be discussed in more detail later in this chapter.

FIGURE 2.4 An Overview of the Synaptic Connections Between Neurons

The arrows represent the directions of the flow of information.

membrane A structure consisting principally of lipid molecules that defines the outer boundaries of a cell and also constitutes many of the cell organelles, such as the Golgi apparatus.

FIGURE 2.5 The Principal Internal Structures of a Multipolar Neuron

The nucleus (“nut”) of the cell is round or oval and is enclosed by the nuclear membrane. The nucleolus and the chromosomes reside here. The nucleolus is responsible for the production of ribosomes , small structures that are involved in protein synthesis. The chromosomes , which consist of long strands of deoxyribonucleic acid (DNA) , contain the organism’s genetic information. When they are active, portions of the chromosomes ( genes ) cause production of another complex molecule, messenger ribonucleic acid (mRNA) , which receives a copy of the information stored at that location. The mRNA leaves the nuclear membrane and attaches to ribosomes, where it causes the production of a particular protein. (See Figure 2.6 . )

nucleus A structure in the central region of a cell, containing the nucleolus and chromosomes.

nucleolus (new clee o lus) A structure within the nucleus of a cell that produces the ribosomes.

ribosome ( ry bo soam) A cytoplasmic structure, made of protein, that serves as the site of production of proteins translated from mRNA.

chromosome A strand of DNA, with associated proteins, found in the nucleus; carries genetic information.

deoxyribonucleic acid (DNA) (dee ox ee ry bo new clay ik) A long, complex macromolecule consisting of two interconnected helical strands; along with associated proteins, strands of DNA constitute the chromosomes.

gene The functional unit of the chromosome, which directs synthesis of one or more proteins.

messenger ribonucleic acid (mRNA) A macromolecule that delivers genetic information concerning the synthesis of a protein from a portion of a chromosome to a ribosome.

Proteins are important in cell functions. As well as providing structure, proteins serve as enzymes , which direct the chemical processes of a cell by controlling chemical reactions. Enzymes are special protein molecules that act as catalysts; that is, they cause a chemical reaction to take place without becoming a part of the final product themselves. Because cells contain the ingredients needed to synthesize an enormous variety of compounds, the ones that cells actually do produce depend primarily on the particular enzymes that are present. Furthermore, there are enzymes that break molecules apart as well as enzymes that put them together; the enzymes that are present in a particular region of a cell thus determine which molecules remain intact. For example,

enzyme A molecule that controls a chemical reaction, combining two substances or breaking a substance into two parts.

In this reversible reaction the relative concentrations of enzymes X and Y determine whether the complex substance AB or its constituents, A and B, will predominate. Enzyme X makes A and B join together; enzyme Y splits AB apart. (Energy may also be required to make the reactions proceed.)

FIGURE 2.6 Protein Synthesis

When a gene is active, a copy of the information is made onto a molecule of messenger RNA. The mRNA leaves the nucleus and attaches to a ribosome, where the protein is produced.

As you undoubtedly know, the sequence of the human genome—along with that of several other plants and animals—has been determined. (The genome is the sequence of nucleotide bases on the chromosomes that provide the information needed to synthesize all the proteins that can be produced by a particular organism.) Biologists were surprised to learn that the number of genes was not correlated with the complexity of the organism (Mattick, 2004 ). For example, Caenorhabditis elegans, a simple worm that consists of about 1000 cells, has 19,000 genes, whereas humans have around 25,000 genes. The research also revealed that the genomes of most vertebrates contained much “junk” DNA, which did not contain information needed to produce proteins. For example, only about 1.5 percent of the human genome encodes for proteins. At first, molecular geneticists assumed that “junk” DNA was a leftover from our evolutionary history and that only the sequences of DNA that encoded for proteins were useful. However, further research found that the amount of non-protein-coding DNA did correlate well with the complexity of an organism and that many of these sequences have been conserved for millions of years. In other words, it started looking as though “junk” DNA was not junk after all. (See Figure 2.7 . )

FIGURE 2.7 Non-coding DNA

This figure shows the percentage of DNA that does not code for proteins in various categories of living organisms.

(Adapted from Mattick, J. S. Scientific American, 2004, 291, 60–67.)

A study by Woolfe et al. ( 2005 ) illustrates the longevity of most non-coding DNA. The researchers compared the genomes of the human and the pufferfish. The common ancestor of these two species lived many millions of years ago, which means that if non-coding DNA is really just useless, leftover junk, then random mutations should have produced many changes in their sequences. However, Woolfe and his colleagues found 1400 highly conserved non-coding sequences, many of which were over 90 percent identical in humans and pufferfish. In addition, they found that these conserved sequences were located near genes that control development, which is unlikely to be a coincidence. In fact, we will see in Chapter 3 that mutations in non-coding regions of the human genome appear to be responsible for the increased size and complexity of the human brain.

What do these non-coding sequences of DNA do? Although their sequences can be transcribed into RNA, this RNA does not result in the production of protein. Instead, non-coding RNA (ncRNA) appears to have functions of it own. For example, when most genes become active, segments of DNA are transcribed into molecules of messenger RNA, and then other molecules cut the mRNA into pieces, discard some parts, and splice the remaining pieces together. The resulting chunk of mRNA then contains the information required for the construction of the protein. The cutting and splicing are accomplished by molecular complexes called spliceosomes, and one of the constituents of spliceosomes is non-coding RNA. Molecules of ncRNA also attach to—and modify—proteins that regulate gene expression (Szymanski et al., 2003 ; Storz, Altuvia, and Wassarman, 2005 ; Satterlee et al., 2007 ). Thus, the human genome, more broadly defined to include non-coding RNA, is much larger than biologists previously believed.

non-coding RNA (ncRNA) A form of RNA that does not encode for protein but has functions of its own.

The bulk of the cell consists of cytoplasm. Cytoplasm is complex and varies considerably across types of cells, but it can most easily be characterized as a jellylike, semiliquid substance that fills the space outlined by the membrane. It contains small, specialized structures, just as the body contains specialized organs. The generic term for these structures is organelle, “little organ.” The most important organelles are described next.

cytoplasm The viscous, semiliquid substance contained in the interior of a cell.

Mitochondria (singular: mitochondrion) are shaped like oval beads and are formed of a double membrane. The inner membrane is wrinkled, and the wrinkles make up a set of shelves (cristae) that fill the inside of the bead. Mitochondria perform a vital role in the economy of the cell; many of the biochemical steps that are involved in the extraction of energy from the breakdown of nutrients take place on the cristae, controlled by enzymes located there. Most cell biologists believe that many eons ago, mitochondria were free-living organisms that came to “infect” larger cells. Because the mitochondria could extract energy more efficiently than the cells they infected, the mitochondria became useful to the cells and eventually became a permanent part of them. Cells provide mitochondria with nutrients, and mitochondria provide cells with a special molecule— adenosine triphosphate (ATP) —that cells use as their immediate source of energy. Mitochondria contain their own DNA and reproduce independently of the cells in which they reside.

mitochondrion An organelle that is responsible for extracting energy from nutrients.

adenosine triphosphate (ATP) (ah den o seen) A molecule of prime importance to cellular energy metabolism; its breakdown liberates energy.

Endoplasmic reticulum , which serves as a storage reservoir and as a channel for transporting chemicals through the cytoplasm, appears in two forms: rough and smooth. Both types consist of parallel layers of membrane, arranged in pairs, of the sort that encloses the cell. Rough endoplasmic reticulum contains ribosomes. The protein produced by the ribosomes that are attached to the rough endoplasmic reticulum is destined to be transported out of the cell or used in the membrane. Unattached ribosomes are also distributed around the cytoplasm; the unattached variety appears to produce protein for use within the neuron. Smooth endoplasmic reticulum provides channels for the segregation of molecules involved in various cellular processes. Lipid (fatlike) molecules are also produced here.

endoplasmic reticulum Parallel layers of membrane found within the cytoplasm of a cell. Rough endoplasmic reticulum contains ribosomes and is involved with production of proteins that are secreted by the cell. Smooth endoplasmic reticulum is the site of synthesis of lipids and provides channels for the segregation of molecules involved in various cellular processes.

The Golgi apparatus is a special form of smooth endoplasmic reticulum. Some complex molecules, made up of simpler individual molecules, are assembled here. The Golgi apparatus also serves as a wrapping or packaging agent. For example, secretory cells (such as those that release hormones) wrap their product in a membrane produced by the Golgi apparatus. When the cell secretes its products, it uses a process called exocytosis (exo, “outside”; cyto, “cell”; -osis, “process”). Briefly stated, the container migrates to the inside of the outer membrane of the cell, fuses with it, and bursts, spilling its contents into the fluid surrounding the cell. As we will see, neurons communicate with one another by secreting chemicals by this means. Therefore, I will describe the process of exocytosis in more detail later in this chapter. The Golgi apparatus also produces lysosomes , small sacs that contain enzymes that break down substances no longer needed by the cell. These products are then recycled or excreted from the cell.

Golgi apparatus ( goal jee) A complex of parallel membranes in the cytoplasm that wraps the products of a secretory cell.

exocytosis ( ex o sy toe sis) The secretion of a substance by a cell through means of vesicles; the process by which neurotransmitters are secreted.

lysosome ( lye so soam) An organelle surrounded by membrane; contains enzymes that break down waste products.

FIGURE 2.8 Fast Axoplasmic Transport

This figure shows how kinesin molecules (a) “walk” down a microtubule, carrying their cargo from the soma to the terminal buttons. Another protein, dynein, carries substances from the terminal buttons to the soma. (b) A photomicrograph of a mouse axon, showing an organelle being transported along a microtubule. The arrow points to what appears to be a kinesin molecule.

If a neuron grown in a tissue culture is exposed to a detergent, the lipid membrane and much of the interior of the cell dissolve away, leaving a matrix of insoluble strands of protein. This matrix, called the cytoskeleton , gives the neuron its shape. The cytoskeleton is made of three kinds of protein strands, linked to each other and forming a cohesive mass. The thickest of these strands, microtubules , are bundles of thirteen protein filaments arranged around a hollow core.

cytoskeleton Formed of microtubules and other protein fibers, linked to each other and forming a cohesive mass that gives a cell its shape.

microtubule (my kro too byool) A long strand of bundles of protein filaments arranged around a hollow core; part of the cytoskeleton and involved in transporting substances from place to place within the cell.

Axons can be extremely long relative to their diameter and the size of the soma. For example, the longest axon in a human stretches from the foot to a region located in the base of the brain. Because terminal buttons need some items that can be produced only in the soma, there must be a system that can transport these items rapidly and efficiently through the axoplasm (that is, the cytoplasm of the axon). This system is referred to as axoplasmic transport , an active process by which substances are propelled along microtubules that run the length of the axon. Movement from the soma to the terminal buttons is called anterograde axoplasmic transport. (Antero- means “toward the front.”) This form of transport is accomplished by molecules of a protein called kinesin. In the cell body, kinesin molecules, which resemble a pair of legs and feet, attach to the item being transported down the axon. The kinesin molecule then walks down a microtubule, carrying the cargo to its destination (Yildiz et al., 2004 ). Energy is supplied by ATP molecules produced by the mitochondria. (See Figure 2.8 . ) Another protein, dynein, carries substances from the terminal buttons to the soma, a process known as retrograde axoplasmic transport. Anterograde axoplasmic transport is remarkably fast: up to 500 mm per day. Retrograde axoplasmic transport is about half as fast as anterograde transport.

axoplasmic transport An active process by which substances are propelled along microtubules that run the length of the axon.

anterograde In a direction along an axon from the cell body toward the terminal buttons.

retrograde In a direction along an axon from the terminal buttons toward the cell body.

Supporting Cells

Neurons constitute only about half the volume of the CNS. The rest consists of a variety of supporting cells. Because neurons have a very high rate of metabolism but have no means of storing nutrients, they must constantly be supplied with nutrients and oxygen or they will quickly die. Thus, the role played by the cells that support and protect neurons is very important to our existence.

GLIA

The most important supporting cells of the central nervous system are the neuroglia, or “nerve glue.” Glia (also called glial cells) do indeed glue the CNS together, but they do much more than that. Neurons lead a very sheltered existence; they are buffered physically and chemically from the rest of the body by the glial cells. Glial cells surround neurons and hold them in place, controlling their supply of nutrients and some of the chemicals they need to exchange messages with other neurons; they insulate neurons from one another so that neural messages do not get scrambled; and they even act as housekeepers, destroying and removing the carcasses of neurons that are killed by disease or injury.

glia ( glee ah) The supporting cells of the central nervous system.

There are several types of glial cells, each of which plays a special role in the CNS. The three most important types are astrocytes, oligodendrocytes, and microglia. Astrocyte means “star cell,” and this name accurately describes the shape of these cells. Astrocytes provide physical support to neurons and clean up debris within the brain. They produce some chemicals that neurons need to fulfill their functions. They help to control the chemical composition of the fluid surrounding neurons by actively taking up or releasing substances whose concentrations must be kept within critical levels. Finally, astrocytes are involved in providing nourishment to neurons.

astrocyte A glial cell that provides support for neurons of the central nervous system, provides nutrients and other substances, and regulates the chemical composition of the extracellular fluid.

Some of the astrocyte’s processes (the arms of the star) are wrapped around blood vessels; other processes are wrapped around parts of neurons, so the somatic and dendritic membranes of neurons are largely surrounded by astrocytes. This arrangement suggested to the Italian histologist Camillo Golgi (1844–1926) that astrocytes supplied neurons with nutrients from the capillaries and disposed of their waste products (Golgi, 1903 ). He thought that nutrients passed from capillaries to the cytoplasm of the astrocytes and then through the cytoplasm to the neurons.

Recent evidence suggests that Golgi was right: Although neurons receive some glucose directly from capillaries, they receive most of their nutrients from astrocytes. Astrocytes receive glucose from capillaries and break it down to lactate, the chemical produced during the first step of glucose metabolism. They then release lactate into the extracellular fluid that surrounds neurons, and neurons take up the lactate, transport it to their mitochondria, and use it for energy (Tsacopoulos and Magistretti, 1996 ; Brown, Tekkök, and Ransom, 2003; Pellerin et al., 2007 ). Apparently, this process provides neurons with a fuel that they can metabolize even more rapidly than glucose. In addition, astrocytes store a small amount of a carbohydrate called glycogen that can be broken down to glucose and then to lactate when the metabolic rate of neurons in their vicinity is especially high. (See Figure 2.9 . )

Besides transporting chemicals to neurons, astrocytes serve as the matrix that holds neurons in place—the “nerve glue,” so to speak. These cells also surround and isolate synapses, limiting the dispersion of neurotransmitters that are released by the terminal buttons.

When cells in the central nervous system die, certain kinds of astrocytes take up the task of cleaning away the debris. These cells are able to travel around the CNS; they extend and retract their processes (pseudopodia, or “false feet”) and glide about the way amoebas do. When these astrocytes contact a piece of debris from a dead neuron, they push themselves against it, finally engulfing and digesting it. We call this process phagocytosis (phagein, “to eat”; kutos, “cell”). If there is a considerable amount of injured tissue to be cleaned up, astrocytes will divide and produce enough new cells to do the task. Once the dead tissue has been broken down, a framework of astrocytes will be left to fill in the vacant area, and a specialized kind of astrocyte will form scar tissue, walling off the area.

phagocytosis ( fagg o sy toe sis) The process by which cells engulf and digest other cells or debris caused by cellular degeneration.

FIGURE 2.9 Structure and Location of Astrocytes

The processes of astrocytes surround capillaries and neurons of the central nervous system.

The principal function of oligodendrocytes is to provide support to axons and to produce the myelin sheath , which insulates most axons from one another. (Very small axons are not myelinated and lack this sheath.) Myelin, 80 percent lipid and 20 percent protein, is produced by the oligodendrocytes in the form of a tube surrounding the axon. This tube does not form a continuous sheath; rather, it consists of a series of segments, each approximately 1 mm long, with a small (1–2 μm) portion of uncoated axon between the segments. (A micrometer, abbreviated μm, is one-millionth of a meter, or one-thousandth of a millimeter.) The bare portion of axon is called a node of Ranvier , after the person who discovered it. The myelinated axon, then, resembles a string of elongated beads. (Actually, the beads are very much elongated—their length is approximately 80 times their width.)

oligodendrocyte (oh li go den droh site) A type of glial cell in the central nervous system that forms myelin sheaths.

myelin sheath ( my a lin) A sheath that surrounds axons and insulates them, preventing messages from spreading between adjacent axons.

node of Ranvier ( raw vee ay) A naked portion of a myelinated axon between adjacent oligodendroglia or Schwann cells.

FIGURE 2.10 Oligodendrocyte

An oligodendrocyte forms the myelin that surrounds many axons in the central nervous system. Each cell forms one segment of myelin for several adjacent axons.

A given oligodendrocyte produces up to fifty segments of myelin. During the development of the CNS, oligodendrocytes form processes shaped something like canoe paddles. Each of these paddle-shaped processes then wraps itself many times around a segment of an axon and, while doing so, produces layers of myelin. Each paddle thus becomes a segment of an axon’s myelin sheath. (See Figures 2.10 and 2.11a . )

FIGURE 2.11 Formation of Myelin

During development a process of an oligodendrocyte or an entire Schwann cell tightly wraps itself many times around an individual axon and forms one segment of the myelin sheath. (a) Oligodendrocyte. (b) Schwann cell.

Dr. C., a retired neurologist, had been afflicted with multiple sclerosis for more than two decades when she died of a heart attack. One evening, twenty-three years previously, she and her husband had had dinner at their favorite restaurant. As they were leaving, she stumbled and almost fell. Her husband joked, “Hey, honey, you shouldn’t have had that last glass of wine.” She smiled at his attempt at humor, but she knew better—her clumsiness wasn’t brought on by the two glasses of wine she had drunk with dinner. She suddenly realized that she had been ignoring some symptoms that she should have recognized.

The next day, she consulted with one of her colleagues, who agreed that her own tentative diagnosis was probably correct: Her symptoms fit those of multiple sclerosis. She had experienced fleeting problems with double vision, she sometimes felt unsteady on her feet, and she occasionally noticed tingling sensations in her right hand. None of these symptoms was serious, and they lasted for only a short while, so she ignored them—or perhaps denied to herself that they were important.

A few weeks after Dr. C.’s death twenty-three years later, a group of medical students and neurological residents gathered in an autopsy room at the medical school. Dr. D., the school’s neuropathologist, displayed a stainless-steel tray on which were lying a brain and a spinal cord. “These belonged to Dr. C.,” he said. “Several years ago she donated her organs to the medical school.” Everyone looked at the brain more intently, knowing that it had animated an esteemed clinician and teacher whom they all knew by reputation, if not personally. Dr. D. led his audience to a set of light boxes on the wall, to which several MRI scans had been clipped. He pointed out some white spots that appeared on one scan. “This scan clearly shows some white-matter lesions, but they are gone on the next one, taken six months later. And here is another one, but it’s gone on the next scan. The immune system attacked the myelin sheaths in a particular region, and then glial cells cleaned up the debris. MRI doesn’t show the lesions then, but the axons can no longer conduct their messages.”

He put on a pair of surgical gloves, picked up Dr. C.’s brain, and cut it in several slices. He picked one up. “Here, see this?” He pointed out a spot of discoloration in a band of white matter. “This is a sclerotic plaque—a patch that feels harder than the surrounding tissue. There are many of them, located throughout the brain and spinal cord, which is why the disease is called multiple sclerosis.” He picked up the spinal cord, felt along its length with his thumb and forefinger, and then stopped and said, “Yes, I can feel a plaque right here.”

Dr. D. put the spinal cord down and said, “Who can tell me the etiology of this disorder?”

One of the students spoke up. “It’s an autoimmune disease. The immune system gets sensitized to the body’s own myelin protein and periodically attacks it, causing a variety of different neurological symptoms. Some say that a childhood viral illness somehow causes the immune system to start seeing the protein as foreign.”

“That’s right,” said Dr. D. “The primary criterion for the diagnosis of multiple sclerosis is the presence of neurological symptoms disseminated in time and space. The symptoms don’t all occur at once, and they can be caused only by damage to several different parts of the nervous system, which means that they can’t be the result of a stroke.”

As their name indicates, microglia are the smallest of the glial cells. Like some types of astrocytes, they act as phagocytes, engulfing and breaking down dead and dying neurons. But, in addition, they serve as one of the representatives of the immune system in the brain, protecting the brain from invading microorganisms. They are primarily responsible for the inflammatory reaction in response to brain damage.

microglia The smallest of glial cells; act as phagocytes and protect the brain from invading microorganisms.

SCHWANN CELLS

In the central nervous system the oligodendrocytes support axons and produce myelin. In the peripheral nervous system the Schwann cells perform the same functions. Most axons in the PNS are myelinated. The myelin sheath occurs in segments, as it does in the CNS; each segment consists of a single Schwann cell, wrapped many times around the axon. In the CNS the oligodendrocytes grow a number of paddle-shaped processes that wrap around a number of axons. In the PNS a Schwann cell provides myelin for only one axon, and the entire Schwann cell—not merely a part of it—surrounds the axon. (See Figure 2.11b . )

Schwann cell A cell in the peripheral nervous system that is wrapped around a myelinated axon, providing one segment of its myelin sheath.

Schwann cells also differ from their CNS counterparts, the oligodendrocytes, in an important way. As we saw, a nerve consists of a bundle of many myelinated axons, all covered in a sheath of tough, elastic connective tissue. If damage occurs to such a nerve, Schwann cells aid in the digestion of the dead and dying axons. Then the Schwann cells arrange themselves in a series of cylinders that act as guides for regrowth of the axons. The distal portions of the severed axons die, but the stump of each severed axon grows sprouts, which then spread in all directions. If one of these sprouts encounters a cylinder provided by a Schwann cell, the sprout will grow through the tube quickly (at a rate of up to 3–4 mm a day), while the other, nonproductive sprouts wither away. If the cut ends of the nerve are still located close enough to each other, the axons will reestablish connections with the muscles and sense organs they previously served.

Unfortunately, the glial cells of the CNS are not as cooperative as the supporting cells of the PNS. If axons in the brain or spinal cord are damaged, new sprouts will form, as in the PNS. However, the budding axons encounter scar tissue produced by the astrocytes, and they cannot penetrate this barrier. Even if the sprouts could get through, the axons would not reestablish their original connections without guidance similar to that provided by the Schwann cells of the PNS. During development, axons have two modes of growth. The first mode causes them to elongate so that they reach their target, which could be as far away as the other end of the brain or spinal cord. Schwann cells provide this signal to injured axons. The second mode causes axons to stop elongating and begin sprouting terminal buttons because they have reached their target. Liuzzi and Lasek ( 1987 ) found that even when astrocytes do not produce scar tissue, they appear to produce a chemical signal that instructs regenerating axons to begin the second mode of growth: to stop elongating and start sprouting terminal buttons. Thus, the difference in the regenerative properties of axons in the CNS and the PNS results from differences in the characteristics of the supporting cells, not from differences in the axons.

There is another difference between oligodendrocytes of the CNS and Schwann cells of the PNS: the chemical composition of the myelin protein they produce. The immune system of someone with multiple sclerosis attacks only the myelin protein produced by oligodendrocytes; thus, the myelin of the peripheral nervous system is spared.

The Blood–Brain Barrier

Over one hundred years ago, Paul Ehrlich discovered that if a blue dye is injected into an animal’s bloodstream, all tissues except the brain and spinal cord will be tinted blue. However, if the same dye is injected into the fluid-filled ventricles of the brain, the blue color will spread throughout the CNS (Bradbury, 1979 ). This experiment demonstrates that a barrier exists between the blood and the fluid that surrounds the cells of the brain: the blood–brain barrier .

blood–brain barrier A semipermeable barrier between the blood and the brain produced by the cells in the walls of the brain’s capillaries.

Some substances can cross the blood–brain barrier; others cannot. Thus, it is selectively permeable (per, “through”; meare, “to pass”). In most of the body the cells that line the capillaries do not fit together absolutely tightly. Small gaps are found between them that permit the free exchange of most substances between the blood plasma and the fluid outside the capillaries that surrounds the cells of the body. In the central nervous system the capillaries lack these gaps; therefore, many substances cannot leave the blood. Thus, the walls of the capillaries in the brain constitute the blood–brain barrier. (See Figure 2.12 . ) Other substances must be actively transported through the capillary walls by special proteins. For example, glucose transporters bring the brain its fuel, and other transporters rid the brain of toxic waste products (Rubin and Staddon, 1999 ; Zlokovic, 2008 ).

What is the function of the blood–brain barrier? As we will see, transmission of messages from place to place in the brain depends on a delicate balance between substances within neurons and those in the extracellular fluid that surrounds them. If the composition of the extracellular fluid is changed even slightly, the transmission of these messages will be disrupted, which means that brain functions will be disrupted. The presence of the blood–brain barrier makes it easier to regulate the composition of this fluid. In addition, many of the foods that we eat contain chemicals that would interfere with the transmission of information between neurons. The blood–brain barrier prevents these chemicals from reaching the brain.

FIGURE 2.12 The Blood–Brain Barrier

This figure shows that (a) the cells that form the walls of the capillaries in the body outside the brain have gaps that permit the free passage of substances into and out of the blood, and (b) the cells that form the walls of the capillaries in the brain are tightly joined.

The blood–brain barrier is not uniform throughout the nervous system. In several places the barrier is relatively permeable, allowing substances that are excluded elsewhere to cross freely. For example, the area postrema is a part of the brain that controls vomiting. The blood–brain barrier is much weaker there, permitting neurons in this region to detect the presence of toxic substances in the blood. (A barrier around the area postrema prevents substances from diffusing from this region into the rest of the brain.) A poison that enters the circulatory system from the stomach can thus stimulate the area postrema to initiate vomiting. If the organism is lucky, the poison can be expelled from the stomach before causing too much damage.

area postrema (poss tree ma) A region of the medulla where the blood–brain barrier is weak; poisons can be detected there and can initiate vomiting.

SECTION SUMMARY: Cells of the Nervous System

Neurons are the most important cells of the nervous system. The central nervous system (CNS) includes the brain and spinal cord; the peripheral nervous system (PNS) includes nerves and some sensory organs.

Neurons have four principal parts: dendrites, soma (cell body), axon, and terminal buttons. They communicate by means of synapses, junctions between the terminal buttons of one neuron and the somatic or dendritic membrane of another. When an action potential travels down an axon, its terminal buttons secrete a chemical that has either an excitatory or an inhibitory effect on the neurons with which they communicate. Ultimately, the effects of these excitatory and inhibitory synapses cause behavior, in the form of muscular contractions.

Neurons contain a quantity of cytoplasm, enclosed in a membrane. Embedded in the membrane are protein molecules that have special functions, such as the detection of hormones or neurotransmitters or transport of particular substances into and out of the cell. The cytoplasm contains the nucleus, which contains the genetic information; the nucleolus (located in the nucleus), which manufactures ribosomes; the ribosomes, which serve as sites of protein synthesis; the endoplasmic reticulum, which serves as a storage reservoir and as a channel for transportation of chemicals through the cytoplasm; the Golgi apparatus, which wraps substances that the cell secretes in a membrane; the lysosomes, which contain enzymes that destroy waste products; microtubules and other protein fibers, which compose the cytoskeleton and help to transport chemicals from place to place; and the mitochondria, which serve as the location for most of the chemical reactions through which the cell extracts energy from nutrients. Recent evidence indicates that only a small proportion of the human genome is devoted to the production of protein; the rest (formerly called “junk” DNA) is involved in the production of non-coding RNA, which has a variety of functions.

Neurons are supported by the glial cells of the central nervous system and the supporting cells of the peripheral nervous system. In the CNS, astrocytes provide support and nourishment, regulate the composition of the fluid that surrounds neurons, and remove debris and form scar tissue in the event of tissue damage. Microglia are phagocytes that serve as the representatives of the immune system. Oligodendrocytes form myelin, the substance that insulates axons, and also support unmyelinated axons. In the PNS, support and myelin are provided by the Schwann cells.

In most organs, molecules freely diffuse between the blood within the capillaries that serve them and the extracellular fluid that bathes their cells. The molecules pass through gaps between the cells that line the capillaries. The walls of the capillaries of the CNS lack these gaps; consequently, fewer substances can enter or leave the brain across the blood–brain barrier.

■ THOUGHT QUESTION

· The fact that the mitochondria in our cells were originally microorganisms that infected our very remote ancestors points out that evolution can involve interactions between two or more species. Many species have other organisms living inside them; in fact, the bacteria in our intestines are necessary for our good health. Some microorganisms can exchange genetic information, so adaptive mutations that develop in one species can be adopted by another. Is it possible that some of the features of the cells of our nervous system were bequeathed to our ancestors by other species?

Communication Within a Neuron

This section describes the nature of communication within a neuron—the way an action potential is sent from the cell body down the axon to the terminal buttons, informing them to release some neurotransmitter. The details of synaptic transmission—the communication between neurons—will be described in the next section. As we will see in this section, an action potential consists of a series of alterations in the membrane of the axon that permit various substances to move between the interior of the axon and the fluid surrounding it. These exchanges produce electrical currents. To see an interactive animation of the information presented in the following section, Simulate the action potentialon MyPsychLab.

Neural Communication: An Overview

Before I begin my discussion of the action potential, let’s step back and see how neurons can interact to produce a useful behavior. We begin by examining a simple assembly of three neurons and a muscle that control a withdrawal reflex. In the next two figures (and in subsequent figures that illustrate simple neural circuits), multipolar neurons are depicted in shorthand fashion as several-sided stars. The points of these stars represent dendrites, and only one or two terminal buttons are shown at the end of the axon. The sensory neuron in this example detects painful stimuli. When its dendrites are stimulated by a noxious stimulus (such as contact with a hot object), it sends messages down the axon to the terminal buttons, which are located in the spinal cord. (You will recognize this cell as a unipolar neuron; see Figure 2.13 . ) The terminal buttons of the sensory neuron release a neurotransmitter that excites the interneuron, causing it to send messages down its axon. The terminal buttons of the interneuron release a neurotransmitter that excites the motor neuron, which sends messages down its axon. The axon of the motor neuron joins a nerve and travels to a muscle. When the terminal buttons of the motor neuron release their neurotransmitter, the muscle cells contract, causing the hand to move away from the hot object. (Look again at Figure 2.13 .)

So far, all of the synapses have had excitatory effects. Now let us complicate matters a bit to see the effect of inhibitory synapses. Suppose you have removed a hot casserole from the oven. As you start walking over to the table to put it down, the heat begins to penetrate the rather thin potholders you are using. The pain caused by the heat triggers a withdrawal reflex that tends to make you drop the casserole. Yet you manage to keep hold of it long enough to get to the table and put it down. What prevented your withdrawal reflex from making you drop the casserole on the floor?

FIGURE 2.13 A Withdrawal Reflex

The figure shows a simple example of a useful function of the nervous system. The painful stimulus causes the hand to pull away from the hot iron.

The pain from the hot casserole increases the activity of excitatory synapses on the motor neurons, which tends to cause the hand to pull away from the casserole. However, this excitation is counteracted by inhibition, supplied by another source: the brain. The brain contains neural circuits that recognize what a disaster it would be if you dropped the casserole on the floor. These neural circuits send information to the spinal cord that prevents the withdrawal reflex from making you drop the dish.

Figure 2.14 shows how this information reaches the spinal cord. As you can see, an axon from a neuron in the brain reaches the spinal cord, where its terminal buttons form synapses with an inhibitory interneuron. When the neuron in the brain becomes active, its terminal buttons excite this inhibitory interneuron. The inter-neuron releases an inhibitory neurotransmitter, which decreases the activity of the motor neuron, blocking the withdrawal reflex. This circuit provides an example of a contest between two competing tendencies: to drop the casserole and to hold onto it. (See Figure 2.14 . )

FIGURE 2.14 The Role of Inhibition

Inhibitory signals arising from the brain can prevent the withdrawal reflex from causing the person to drop the casserole.

Of course, reflexes are more complicated than this description, and the mechanisms that inhibit them are even more so. And thousands of neurons are involved in this process. The five neurons shown in Figure 2.14 represent many others: Dozens of sensory neurons detect the hot object, hundreds of interneurons are stimulated by their activity, hundreds of motor neurons produce the contraction—and thousands of neurons in the brain must become active if the reflex is to be inhibited. Yet this simple model provides an overview of the process of neural communication, which is described in more detail later in this chapter.

Measuring Electrical Potentials of Axons

Let’s examine the nature of the message that is conducted along the axon. To do so, we obtain an axon that is large enough to work with. Fortunately, nature has provided the neuroscientist with the giant squid axon (the giant axon of a squid, not the axon of a giant squid!). This axon is about 0.5 mm in diameter, which is hundreds of times larger than the largest mammalian axon. (This large axon controls an emergency response: sudden contraction of the mantle, which squirts water through a jet and propels the squid away from a source of danger.) We place an isolated giant squid axon in a dish of seawater, in which it can exist for a day or two.

To measure the electrical charges generated by an axon, we will need to use a pair of electrodes. Electrodes are electrical conductors that provide a path for electricity to enter or leave a medium. One of the electrodes is a simple wire that we place in the seawater. The other one, which we use to record the message from the axon, has to be special. Because even a giant squid axon is rather small, we must use a tiny electrode that will record the membrane potential without damaging the axon. To do so, we use a microelectrode.

electrode A conductive medium that can be used to apply electrical stimulation or to record electrical potentials.

A microelectrode is simply a very small electrode, which can be made of metal or glass. In this case we will use one made of thin glass tubing, which is heated and drawn down to an exceedingly fine point, less than a thousandth of a millimeter in diameter. Because glass will not conduct electricity, the glass microelectrode is filled with a liquid that conducts electricity, such as a solution of potassium chloride.

microelectrode A very fine electrode, generally used to record activity of individual neurons.

We place the wire electrode in the seawater and insert the microelectrode into the axon. (See Figure 2.15a . ) As soon as we do so, we discover that the inside of the axon is negatively charged with respect to the outside; the difference in charge being 70 mV (millivolts, or thousandths of a volt). Thus, the inside of the membrane is –70 mV. This electrical charge is called the membrane potential . The term potentialrefers to a stored-up source of energy—in this case, electrical energy. For example, a flashlight battery that is not connected to an electrical circuit has a potential charge of 1.5 V between its terminals. If we connect a light bulb to the terminals, the potential energy is tapped and converted into radiant energy (light). (See Figure 2.15b . ) Similarly, if we connect our electrodes—one inside the axon and one outside it—to a very sensitive voltmeter, we will convert the potential energy to movement of the meter’s needle. Of course, the potential electrical energy of the axonal membrane is very weak in comparison with that of a flashlight battery.

membrane potential The electrical charge across a cell membrane; the difference in electrical potential inside and outside the cell.

FIGURE 2.15 Measuring Electrical Charge

The figure shows (a) a voltmeter detecting the charge across a membrane of an axon and (b) a light bulb detecting the charge across the terminals of a battery.

As we will see, the message that is conducted down the axon consists of a brief change in the membrane potential. However, this change occurs very rapidly—too rapidly for us to see if we were using a voltmeter. Therefore, to study the message, we will use an oscilloscope . This device, like a voltmeter, measures voltages, but it also produces a record of these voltages, graphing them as a function of time. These graphs are displayed on a screen, much like the one found in a television. The vertical axis represents voltage, and the horizontal axis represents time, going from left to right.

oscilloscope A laboratory instrument that is capable of displaying a graph of voltage as a function of time on the face of a cathode ray tube.

FIGURE 2.16 Studying the Axon

The figure shows the means by which an axon can be stimulated while its membrane potential is being recorded.

Once we insert our microelectrode into the axon, the oscilloscope draws a straight horizontal line at –70 mV, as long as the axon is not disturbed. This electrical charge across the membrane is called, quite appropriately, the resting potential . Now let us disturb the resting potential and see what happens. To do so, we will use another device—an electrical stimulator that allows us to alter the membrane potential at a specific location. (See Figure 2.16 . ) The stimulator can pass current through another microelectrode that we have inserted into the axon. Because the inside of the axon is negative, a positive charge applied to the inside of the membrane produces a depolarization . That is, it takes away some of the electrical charge across the membrane near the electrode, reducing the membrane potential.

resting potential The membrane potential of a neuron when it is not being altered by excitatory or inhibitory postsynaptic potentials; approximately –70 mV in the giant squid axon.

depolarization Reduction (toward zero) of the membrane potential of a cell from its normal resting potential.

Let us see what happens to an axon when we artificially change the membrane potential at one point. Figure 2.17 shows a graph drawn by an oscilloscope that has been monitoring the effects of brief depolarizing stimuli. The graphs of the effects of these separate stimuli are superimposed on the same drawing so that we can compare them. We deliver a series of depolarizing stimuli, starting with a very weak stimulus (number 1) and gradually increasing their strength. Each stimulus briefly depolarizes the membrane potential a little more. Finally, after we present depolarization number 4, the membrane potential suddenly reverses itself, so the inside becomes positive (and the outside becomes negative). The membrane potential quickly returns to normal, but first it overshoots the resting potential, becoming hyperpolarized —more polarized than normal—for a short time. The whole process takes about 2 msec (milliseconds). (See Figure 2.17 . )

hyperpolarization An increase in the membrane potential of a cell, relative to the normal resting potential.

FIGURE 2.17 An Action Potential

These results would be seen on an oscilloscope screen if depolarizing stimuli of varying intensities were delivered to the axon shown in Figure 2.16 .

This phenomenon, a very rapid reversal of the membrane potential, is called the action potential . It constitutes the message carried by the axon from the cell body to the terminal buttons. The voltage level that triggers an action potential—which was achieved only by depolarizing shock number 4—is called the threshold of excitation .

action potential The brief electrical impulse that provides the basis for conduction of information along an axon.

threshold of excitation The value of the membrane potential that must be reached to produce an action potential.

The Membrane Potential: Balance of Two Forces

To understand what causes the action potential to occur, we must first understand the reasons for the existence of the membrane potential. As we will see, this electrical charge is the result of a balance between two opposing forces: diffusion and electrostatic pressure.

THE FORCE OF DIFFUSION

When a spoonful of sugar is carefully poured into a container of water, it settles to the bottom. After a time the sugar dissolves, but it remains close to the bottom of the container. After a much longer time (probably several days) the molecules of sugar distribute themselves evenly throughout the water, even if no one stirs the liquid. The process whereby molecules distribute themselves evenly throughout the medium in which they are dissolved is called diffusion .

diffusion Movement of molecules from regions of high concentration to regions of low concentration.

When there are no forces or barriers to prevent them from doing so, molecules will diffuse from regions of high concentration to regions of low concentration. Molecules are constantly in motion, and their rate of movement is proportional to the temperature. Only at absolute zero [0 K (kelvin) = −273.15°C = −459.7°F] do molecules cease their random movement. At all other temperatures they move about, colliding and veering off in different directions, thus pushing one another away. The result of these collisions in the example of sugar and water is to force sugar molecules upward (and to force water molecules downward), away from the regions in which they are most concentrated.

THE FORCE OF ELECTROSTATIC PRESSURE

When some substances are dissolved in water, they split into two parts, each with an opposing electrical charge. Substances with this property are called electrolytes ; the charged particles into which they decompose are called ions . Ions are of two basic types: Cations have a positive charge, and anions have a negative charge. For example, when sodium chloride (NaCl, table salt) is dissolved in water, many of the molecules split into sodium cations (Na+) and chloride anions (Cl−). (I find that the easiest way to keep the terms cation and anion straight is to think of the cation’s plus sign as a cross and remember the superstition of a black cat crossing your path.)

electrolyte An aqueous solution of a material that ionizes—namely, a soluble acid, base, or salt.

ion A charged molecule. Cations are positively charged, and anions are negatively charged.

As you have undoubtedly learned, particles with the same kind of charge repel each other (+ repels +, and − repels −), but particles with different charges are attracted to each other (+ and − attract). Thus, anions repel anions, cations repel cations, but anions and cations attract each other. The force exerted by this attraction or repulsion is called electrostatic pressure . Just as the force of diffusion moves molecules from regions of high concentration to regions of low concentration, electrostatic pressure moves ions from place to place: Cations are pushed away from regions with an excess of cations, and anions are pushed away from regions with an excess of anions.

electrostatic pressure The attractive force between atomic particles charged with opposite signs or the repulsive force between atomic particles charged with the same sign.

IONS IN THE EXTRACELLULAR AND INTRACELLULAR FLUID

The fluid within cells ( intracellular fluid ) and the fluid surrounding them ( extracellular fluid ) contain different ions. The forces of diffusion and electrostatic pressure contributed by these ions give rise to the membrane potential. Because the membrane potential is produced by a balance between the forces of diffusion and electrostatic pressures, understanding what produces this potential requires that we know the concentration of the various ions in the extracellular and intracellular fluids.

intracellular fluid The fluid contained within cells.

extracellular fluid Body fluids located outside of cells.

There are several important ions in these fluids. I will discuss four of them here: organic anions (symbolized by A−), chloride ions (Cl−), sodium ions (Na+), and potassium ions (K+). The Latin words for sodium and potassium are natrium and kalium; hence, they are abbreviated Na and K, respectively. Organic anions—negatively charged proteins and intermediate products of the cell’s metabolic processes—are found only in the intracellular fluid. Although the other three ions are found in both the intracellular and extracellular fluids, K+ is found predominantly in the intracellular fluid, whereas Na+and Cl− are found predominantly in the extracellular fluid. The sizes of the boxes in Figure 2.18 indicate the relative concentrations of these four ions. (See Figure 2.18 . ) The easiest way to remember which ion is found where is to recall that the fluid that surrounds our cells is similar to seawater, which is predominantly a solution of salt, NaCl. The primitive ancestors of our cells lived in the ocean; thus, the seawater was their extracellular fluid. Our extracellular fluid thus resembles seawater, produced and maintained by regulatory mechanisms that are described in Chapter 12 .

Let us consider the ions in Figure 2.18 , examining the forces of diffusion and electrostatic pressure exerted on each and reasoning why each is located where it is. A−, the organic anion, is unable to pass through the membrane of the axon; therefore, although the presence of this ion within the cell contributes to the membrane potential, it is located where it is because the membrane is impermeable to it.

FIGURE 2.18 Control of the Membrane Potential

The figure shows the relative concentration of some important ions inside and outside the neuron and the forces acting on them.

The potassium ion K+ is concentrated within the axon; thus, the force of diffusion tends to push it out of the cell. However, the outside of the cell is charged positively with respect to the inside, so electrostatic pressure tends to force this cation inside. Thus, the two opposing forces balance, and potassium ions tend to remain where they are. (Refer again to Figure 2.18 .)

The chloride ion Cl− is in greatest concentration outside the axon. The force of diffusion pushes this ion inward. However, because the inside of the axon is negatively charged, electrostatic pressure pushes this anion outward. Again, two opposing forces balance each other. (Look again at Figure 2.18 .)

The sodium ion Na+ is also in greatest concentration outside the axon, so it, like Cl−, is pushed into the cell by the force of diffusion. But unlike chloride, the sodium ion is positively charged. Therefore, electrostatic pressure does not prevent Na+ from entering the cell; indeed, the negative charge inside the axon attractsNa+. (Look once more at Figure 2.18 .)

How can Na+ remain in greatest concentration in the extracellular fluid, despite the fact that both forces (diffusion and electrostatic pressure) tend to push it inside? The answer is this: Another force, provided by the sodium–potassium pump, continuously pushes Na+ out of the axon. The sodium–potassium pump consists of a large number of protein molecules embedded in the membrane, driven by energy provided by molecules of ATP produced by the mitochondria. These molecules, known as sodium–potassium transporters , exchange Na+ for K+, pushing three sodium ions out for every two potassium ions they push in. (See Figure 2.19 . )

sodium–potassium transporter A protein found in the membrane of all cells that extrudes sodium ions from and transports potassium ions into the cell.

Because the membrane is not very permeable to Na+, sodium–potassium transporters very effectively keep the intracellular concentration of Na+ low. By transporting K+ into the cell, they also increase the intracellular concentration of K+ a small amount. The membrane is approximately 100 times more permeable to K+ than to Na+, so the increase is slight; but, as we will see when we study the process of neural inhibition later in this chapter, it is very important. The transporters that make up the sodium–potassium pump use considerable energy: Up to 40 percent of a neuron’s metabolic resources are used to operate them. Neurons, muscle cells, glia—in fact, most cells of the body—have sodium–potassium transporters in their membrane.

The Action Potential

As we saw, the forces of both diffusion and electrostatic pressure tend to push Na+ into the cell. However, the membrane is not very permeable to this ion, and sodium–potassium transporters continuously pump out Na+, keeping the intracellular level of Na+ low. But imagine what would happen if the membrane suddenly became permeable to Na+. The forces of diffusion and electrostatic pressure would cause Na+ to rush into the cell. This sudden influx (inflow) of positively charged ions would drastically change the membrane potential. Indeed, experiments have shown that this mechanism is precisely what causes the action potential: A brief increase in the permeability of the membrane to Na+ (allowing these ions to rush into the cell) is immediately followed by a transient increase in the permeability of the membrane to K+(allowing these ions to rush out of the cell). What is responsible for these transient increases in permeability?

FIGURE 2.19 A Sodium–Potassium Transporter

These transporters are found in the cell membrane.

We already saw that one type of protein molecule embedded in the membrane—the sodium–potassium transporter—actively pumps sodium ions out of the cell and pumps potassium ions into it. Another type of protein molecule provides an opening that permits ions to enter or leave the cells. These molecules provide ion channels , which contain passages (“pores”) that can open or close. When an ion channel is open, a particular type of ion can flow through the pore and thus can enter or leave the cell. (See Figure 2.20 . ) Neural membranes contain many thousands of ion channels. For example, the giant squid axon contains several hundred sodium channels in each square micrometer of membrane. (There are one million square micrometers in a square millimeter; thus, a patch of axonal membrane the size of a lowercase letter o in this book would contain several hundred million sodium channels.) Each sodium channel can admit up to 100 million ions per second when it is open. Thus, the permeability of a membrane to a particular ion at a given moment is determined by the number of ion channels that are open.

ion channel A specialized protein molecule that permits specific ions to enter or leave cells.

FIGURE 2.20 Ion Channels

When ion channels are open, ions can pass through them, entering or leaving the cell.

The following numbered paragraphs describe the movements of ions through the membrane during the action potential. The numbers in the figure correspond to the numbers of the paragraphs that follow. (See Figure 2.21 . )

FIGURE 2.21 Ion Movements During the Action Potential

The shaded box at the top shows the opening of sodium channels at the threshold of excitation, their refractory condition at the peak of the action potential, and their resetting when the membrane potential returns to normal.

· 1. As soon as the threshold of excitation is reached, the sodium channels in the membrane open, and Na+ rushes in, propelled by the forces of diffusion and electrostatic pressure. The opening of these channels is triggered by reduction of the membrane potential (depolarization); they open at the point at which an action potential begins: the threshold of excitation. Because these channels are opened by changes in the membrane potential, they are called voltage-dependent ion channels . The influx of positively charged sodium ions produces a rapid change in the membrane potential, from −70 mV to + 40 mV.

voltage-dependent ion channel An ion channel that opens or closes according to the value of the membrane potential.

· 2. The membrane of the axon contains voltage-dependent potassium channels, but these channels are less sensitive than voltage-dependent sodium channels. That is, they require a greater level of depolarization before they begin to open. Thus, they begin to open later than the sodium channels.

FIGURE 2.22 Permeability to Ions During the Action Potential

The graph shows changes in the permeability of the membrane of an axon to Na+ and K+ during the action potential.

· 3. At about the time the action potential reaches its peak (in approximately 1 msec), the sodium channels become refractory—the channels become blocked and cannot open again until the membrane once more reaches the resting potential. At this time, no more Na+ can enter the cell.

· 4. By now, the voltage-dependent potassium channels in the membrane are open, letting K+ ions move freely through the membrane. At this time, the inside of the axon is positively charged, so K+ is driven out of the cell by diffusion and by electrostatic pressure. This outflow of cations causes the membrane potential to return toward its normal value. As it does so, the potassium channels begin to close again.

· 5. Once the membrane potential returns to normal, the sodium channels reset so that another depolarization can cause them to open again.

· 6. The membrane actually overshoots its resting value (−70 mV) and only gradually returns to normal as the potassium channels finally close. Eventually, sodium–potassium transporters remove the Na+ions that leaked in and retrieve the K+ ions that leaked out.

Figure 2.22 illustrates the changes in permeability of the membrane to sodium and potassium ions during the action potential. (See Figure 2.22 . )

How much ionic flow is there? The increased permeability of the membrane to Na+ is brief, and diffusion over any appreciable distance takes some time. Thus, when I say, “Na+ rushes in,” I do not mean that the axoplasm becomes flooded with Na+. At the peak of the action potential a very thin layer of fluid immediately inside the axon becomes full of newly arrived Na+ ions; this amount is indeed enough to reverse the membrane potential. However, not enough time has elapsed for these ions to fill the entire axon. Before that event can take place, the Na+ channels close, and K+ starts flowing out.

Experiments have shown that an action potential temporarily increases the number of Na+ ions inside the giant squid axon by 0.0003 percent. Although the concentration just inside the membrane is high, the total number of ions entering the cell is very small relative to the number already there. This means that, on a short-term basis, sodium–potassium transporters are not very important. The few Na+ ions that manage to leak in diffuse into the rest of the axoplasm, and the slight increase in Na+ concentration is hardly noticeable. However, sodium–potassium transporters are important on a long-term basis. Without the activity of sodium–potassium transporters, the concentration of sodium ions in the axoplasm would eventually increase enough that the axon would no longer be able to function.

Conduction of the Action Potential

Now that we have a basic understanding of the resting membrane potential and the production of the action potential, we can consider the movement of the message down the axon, or conduction of the action potential. To study this phenomenon, we again make use of the giant squid axon. We attach an electrical stimulator to an electrode at one end of the axon and place recording electrodes, attached to oscilloscopes, at different distances from the stimulating electrode. Then we apply a depolarizing stimulus to the end of the axon and trigger an action potential. We record the action potential from each of the electrodes, one after the other. Thus, we see that the action potential is conducted down the axon. As the action potential travels, it remains constant in size. (See Figure 2.23 . )

This experiment establishes a basic law of axonal conduction: the all-or-none law . This law states that an action potential either occurs or does not occur; and, once triggered, it is transmitted down the axon to its end. An action potential always remains the same size, without growing or diminishing. And when an action potential reaches a point where the axon branches, it splits but does not diminish in size. An axon will transmit an action potential in either direction, or even in both directions, if it is started in the middle of the axon’s length. However, because action potentials in living animals start at the end attached to the soma, axons normally carry one-way traffic.

all-or-none law The principle that once an action potential is triggered in an axon, it is propagated, without decrement, to the end of the fiber.

As you know, the strength of a muscular contraction can vary from very weak to very forceful, and the strength of a stimulus can vary from barely detectable to very intense. We know that the occurrence of action potentials in axons controls the strength of muscular contractions and represents the intensity of a physical stimulus. But if the action potential is an all-or-none event, how can it represent information that can vary in a continuous fashion? The answer is simple: A single action potential is not the basic element of information; rather, variable information is represented by an axon’s rate of firing. (In this context, firing refers to the production of action potentials.) A high rate of firing causes a strong muscular contraction, and a strong stimulus (such as a bright light) causes a high rate of firing in axons that serve the eyes. Thus, the all-or-none law is supplemented by the rate law . (See Figure 2.24 . )

rate law The principle that variations in the intensity of a stimulus or other information being transmitted in an axon are represented by variations in the rate at which that axon fires.

FIGURE 2.23 Conduction of the Action Potential

When an action potential is triggered, its size remains undiminished as it travels down the axon. The speed of conduction can be calculated from the delay between the stimulus and the action potential.

Recall that all but the smallest axons in mammalian nervous systems are myelinated; segments of the axons are covered by a myelin sheath produced by the oligodendrocytes of the CNS or the Schwann cells of the PNS. These segments are separated by portions of naked axon, the nodes of Ranvier. Conduction of an action potential in a myelinated axon is somewhat different from conduction in an unmyelinated axon.

Schwann cells and the oligodendrocytes of the CNS wrap tightly around the axon, leaving no measurable extracellular fluid between them and the axon. The only place where a myelinated axon comes into contact with the extracellular fluid is at a node of Ranvier, where the axon is naked. In the myelinated areas there can be no inward flow of Na+ when the sodium channels open because there is no extracellular sodium. The axon conducts the electrical disturbance from the action potential to the next node of Ranvier. The disturbance is conducted passively, the way an electrical signal is conducted through an insulated cable. The disturbance gets smaller as it passes down the axon, but it is still large enough to trigger a new action potential at the next node. (This decrease in the size of the disturbance is called decremental conduction.) The action potential gets retriggered, or repeated, at each node of Ranvier, and the electrical disturbance that results is conducted decrementally along the myelinated area to the next node. Transmission of this message, hopping from node to node, is called saltatory conduction , from the Latin saltare, “to dance.” (See Figure 2.25 . )

saltatory conduction Conduction of action potentials by myelinated axons. The action potential appears to jump from one node of Ranvier to the next.

FIGURE 2.24 The Rate Law

The strength of a stimulus is represented by the rate of firing of an axon. The size of each action potential is always constant.

Saltatory conduction confers two advantages. The first is economic. Sodium ions enter axons during action potentials, and these ions must eventually be removed. Sodium–potassium transporters must be located along the entire length of unmyelinated axons because Na+ enters everywhere. However, because Na+ can enter myelinated axons only at the nodes of Ranvier, much less gets in, and consequently much less has to be pumped out again. Therefore, myelinated axons expend much less energy to maintain their sodium balance.

The second advantage to myelin is speed. Conduction of an action potential is faster in a myelinated axon because the transmission between the nodes is very fast. Increased speed enables an animal to react faster and (undoubtedly) to think faster. One of the ways to increase the speed of conduction is to increase size. Because it is so large, the unmyelinated squid axon, with a diameter of 500 μm, achieves a conduction velocity of approximately 35 m/sec (meters per second). However, a myelinated cat axon achieves the same speed with a diameter of a mere 6 μm. The fastest myelinated axon, 20 μm in diameter, can conduct action potentials at a speedy 120 m/sec, or 432 km/h (kilometers per hour). At that speed a signal can get from one end of an axon to the other without much delay.

FIGURE 2.25 Saltatory Conduction

The figure shows propagation of an action potential down a myelinated axon.

SECTION SUMMARY: Communication Within a Neuron

The withdrawal reflex illustrates how neurons can be connected to accomplish useful behaviors. The circuit responsible for this reflex consists of three sets of neurons: sensory neurons, interneurons, and motor neurons.

The reflex can be suppressed when neurons in the brain activate inhibitory interneurons that form synapses with the motor neurons.

The message that is conducted down an axon is called an action potential. The membranes of all cells of the body are electrically charged, but only axons can produce action potentials. The resting membrane potential occurs because various ions are located in different concentrations in the fluid inside and outside the cell. The extracellular fluid (like seawater) is rich in Na+ and Cl−, and the intracellular fluid is rich in K+ and various organic anions, designated as A−.

The cell membrane is freely permeable to water, but its permeability to various ions—in particular, Na+and K+—is regulated by ion channels. When the membrane potential is at its resting value (–70 mV), the voltage-dependent sodium and potassium channels are closed. Some Na+ continuously leaks into the axon but is promptly forced out of the cell again by the sodium–potassium transporters (which also pump potassium into the axon). When an electrical stimulator depolarizes the membrane of the axon so that its potential reaches the threshold of excitation, voltage-dependent sodium channels open, and Na+ rushes into the cell, driven by the force of diffusion and by electrostatic pressure. The entry of these positively charged ions further reduces the membrane potential and, indeed, causes it to reverse, so the inside becomes positive. The opening of the sodium channels is temporary; they soon close again. The depolarization caused by the influx of Na+ activates voltage-dependent potassium channels, and K+ leaves the axon, traveling down its concentration gradient. This efflux (outflow) of K+ quickly brings the membrane potential back to its resting value.

Because an action potential of a given axon is an all-or-none phenomenon, neurons represent intensity by their rate of firing. The action potential normally begins at one end of the axon, where the axon attaches to the soma. The action potential travels continuously down unmyelinated axons, remaining constant in size, until it reaches the terminal buttons. (If the axon divides, an action potential continues down each branch.) In myelinated axons, ions can flow through the membrane only at the nodes of Ranvier, because the axons are covered everywhere else with myelin, which isolates them from the extracellular fluid. Thus, the action potential is conducted passively from one node of Ranvier to the next. When the electrical message reaches a node, voltage-dependent sodium channels open, and a new action potential is triggered. This mechanism saves a considerable amount of energy because sodium–potassium transporters are not needed along the myelinated portions of the axon, and saltatory conduction is faster.

■ THOUGHT QUESTION

· The evolution of the human brain, with all its complexity, depended on many apparently trivial mechanisms. For example, what if cells had not developed the ability to manufacture myelin? Unmyelinated axons must be very large if they are to transmit action potentials rapidly. How big would the human brain have to be if oligodendrocytes did not produce myelin? Could the human brain as we know it have evolved without myelin?

Communication Between Neurons

Now that you know about the basic structure of neurons and the nature of the action potential, it is time to describe the ways in which neurons can communicate with each other. These communications make it possible for circuits of neurons to gather sensory information, make plans, and initiate behaviors.

The primary means of communication between neurons is synaptic transmission—the transmission of messages from one neuron to another through a synapse. As we saw, these messages are carried by neurotransmitters, released by terminal buttons. These chemicals diffuse across the fluid-filled gap between the terminal buttons and the membranes of the neurons with which they form synapses. As we will see in this section, neurotransmitters produce postsynaptic potentials —brief depolarizations or hyperpolarizations—that increase or decrease the rate of firing of the axon of the postsynaptic neuron. To see an interactive animation of the information presented in the following section, Simulatesynapses on MyPsychLab.

postsynaptic potential Alterations in the membrane potential of a postsynaptic neuron, produced by liberation of neurotransmitter at the synapse.

Neurotransmitters exert their effects on cells by attaching to a particular region of a receptor molecule called the binding site . A molecule of the chemical fits into the binding site the way a key fits into a lock: The shape of the binding site and the shape of the molecule of the neurotransmitter are complementary. A chemical that attaches to a binding site is called a ligand , from ligare, “to bind.” Neurotransmitters are natural ligands, produced and released by neurons. But other chemicals found in nature (primarily in plants or in the poisonous venoms of animals) can serve as ligands too. In addition, artificial ligands can be produced in the laboratory. These chemicals are discussed in Chapter 4 , which deals with drugs and their effects.

binding site The location on a receptor protein to which a ligand binds.

ligand (lye gand or ligg and) A chemical that binds with the binding site of a receptor.

Structure of Synapses

As you have already learned, synapses are junctions between the terminal buttons at the ends of the axonal branches of one neuron and the membrane of another. Synapses can occur in three places: on dendrites, on the soma, and on other axons. These synapses are referred to as axodendritic, axosomatic, and axoaxonic. Axodendritic synapses can occur on the smooth surface of a dendrite or on dendritic spines —small protrusions that stud the dendrites of several types of large neurons in the brain. (See Figure 2.26 . )

dendritic spine A small bud on the surface of a dendrite, with which a terminal button of another neuron forms a synapse.

Figure 2.27 illustrates a synapse. The presynaptic membrane , located at the end of the terminal button, faces the postsynaptic membrane , located on the neuron that receives the message (the postsynapticneuron). These two membranes face each other across the synaptic cleft , a gap that varies in size from synapse to synapse but is usually around 20 nm wide. (A nanometer, nm, is one billionth of a meter.) The synaptic cleft contains extracellular fluid, through which the neurotransmitter diffuses. A meshwork of filaments crosses the synaptic cleft and keeps the presynaptic and postsynaptic membranes in alignment. (See Figure 2.27 . )

presynaptic membrane The membrane of a terminal button that lies adjacent to the postsynaptic membrane and through which the neurotransmitter is released.

postsynaptic membrane The cell membrane opposite the terminal button in a synapse; the membrane of the cell that receives the message.

synaptic cleft The space between the presynaptic membrane and the postsynaptic membrane.

FIGURE 2.26 Types of Synapses

Axodendritic synapses can occur on the smooth surface of a dendrite (a) or on dendritic spines (b). Axosomatic synapses occur on somatic membrane (c). Axoaxonic synapses consist of synapses between two terminal buttons (d).

As you may have noticed in Figure 2.27 , two prominent structures are located in the cytoplasm of the terminal button: mitochondria and synaptic vesicles. We also see microtubules, which are responsible for transporting material between the soma and terminal button. The presence of mitochondria implies that the terminal button needs energy to perform its functions. Synaptic vesicles are small, rounded objects in the shape of spheres or ovoids. (The term vesicle means “little bladder.”) A given terminal button can contain from a few hundred to nearly a million synaptic vesicles. Many terminal buttons contain two types of synaptic vesicles: large and small. Small synaptic vesicles (found in all terminal buttons) contain molecules of the neurotransmitter. They range in number from a few dozen to several hundred. The membrane of small synaptic vesicles consists of approximately 10,000 lipid molecules into which are inserted about 200 protein molecules. Transport proteins fill vesicles with the neurotransmitter, and trafficking proteins are involved in the release of neurotransmitter and recycling of the vesicles. Synaptic vesicles are found in greatest numbers around the part of the presynaptic membrane that faces the synaptic cleft—near the release zone , the region from which the neurotransmitter is released. In many terminal buttons we see a scattering of large, dense-core synaptic vesicles. These vesicles contain one of a number of different peptides, the functions of which are described later in this chapter. (See Figures 2.27 and 2.28 . )

synaptic vesicle (vess i kul) A small, hollow, beadlike structure found in terminal buttons; contains molecules of a neurotransmitter.

release zone A region of the interior of the presynaptic membrane of a synapse to which synaptic vesicles attach and release their neurotransmitter into the synaptic cleft.

FIGURE 2.27 Details of a Synapse

Small synaptic vesicles are produced in the Golgi apparatus located in the soma and are carried by fast axoplasmic transport to the terminal button. As we will see, some are also produced from recycled material in the terminal button. Large synaptic vesicles are produced only in the soma and are transported through the axoplasm to the terminal buttons.

In an electron micrograph the postsynaptic membrane under the terminal button appears somewhat thicker and more dense than the membrane elsewhere. This postsynaptic density is caused by the presence of receptors—specialized protein molecules that detect the presence of neurotransmitters in the synaptic cleft—and protein filaments that hold the receptors in place. (Look again at Figures 2.27 and 2.28 . )

FIGURE 2.28 Cross Section of a Synapse

The photograph from an electron microscope shows a cross section of a synapse. The terminal button contains many synaptic vesicles, filled with the neurotransmitter, and a single large dense-core vesicle, filled with a peptide.

(From De Camilli et al., in Synapses, edited by W. M. Cowan, T. C. Südhof, and C. F. Stevens. Baltimore, MD: Johns Hopkins University Press, 2001. Reprinted with permission.)

Release of Neurotransmitter

When action potentials are conducted down an axon (and down all of its branches), something happens inside all of the terminal buttons: A number of small synaptic vesicles located just inside the presynaptic membrane fuse with the membrane and then break open, spilling their contents into the synaptic cleft. Figure 2.29 shows a portion of a frog’s neuromuscular junction—the synapse between a terminal button and a muscle fiber. The axon has just been stimulated, and synaptic vesicles in the terminal button are in the process of releasing the neurotransmitter. Note that some vesicles are fused with the presynaptic membrane, forming the shape of an omega (Ω). (See Figure 2.29 . )

How does an action potential cause synaptic vesicles to release the neurotransmitter? The process begins when a population of synaptic vesicles become “docked” against the presynaptic membrane, ready to release their neurotransmitter into the synaptic cleft. Docking is accomplished when clusters of protein molecules attach to other protein molecules located in the presynaptic membrane. (See Figure 2.30 . )

FIGURE 2.29 Cross Section of a Synapse

The photograph from an electron microscope shows a cross section of a synapse. The omega-shaped figures are synaptic vesicles fusing with the presynaptic membranes of terminal buttons that form synapses with frog muscle.

(From Heuser, J. E., in Society for Neuroscience Symposia, Vol. II, edited by W. M. Cowan and J. A. Ferrendelli. Bethesda, MD: Society for Neuroscience, 1977. Reprinted with permission.)

FIGURE 2.30 Release of Neurotransmitter

An action potential opens calcium channels, which enter and bind with the protein embedded in the membrane of synaptic vesicles docked at the release zone. The fusion pores open, and the neurotransmitter is released into the synaptic cleft.

The release zone of the presynaptic membrane contains voltage-dependent calcium channels. When the membrane of the terminal button is depolarized by an arriving action potential, the calcium channels open. Like sodium ions, calcium ions (Ca2+) are located in highest concentration in the extracellular fluid. Thus, when the voltage-dependent calcium channels open, Ca2+ flows into the cell, propelled by electrostatic pressure and the force of diffusion. The entry of Ca2+ is an essential step; if neurons are placed in a solution that contains no calcium ions, an action potential no longer causes the release of the neurotransmitter. (Calcium transporters, similar in operation to sodium–potassium transporters, later remove the intracellular Ca2+.)

As we will see later in this chapter and in subsequent chapters of this book, calcium ions play many important roles in biological processes within cells. Calcium ions can bind with various types of proteins, changing their characteristics. Some of the calcium ions that enter the terminal button bind with the clusters of protein molecules that join the membrane of the synaptic vesicles with the presynaptic membrane. This event makes the segments of the clusters of protein molecules move apart, producing a fusion pore—a hole through both membranes that enables them to fuse together. The process of fusion takes approximately 0.1 msec. (Look again at Figure 2.30 .)

Figure 2.31 shows two photomicrographs of the presynaptic membrane, before and after the fusion pores have opened. We see the face of the presynaptic membrane as it would be viewed from the postsynaptic membrane. As you can see, the synaptic vesicles are aligned in a row along the release zone. The small bumps arranged in lines on each side of the synaptic vesicles appear to be voltage-dependent calcium channels. (See Figure 2.31 . )

Research indicates that there are three distinct pools of synaptic vesicles (Rizzoli and Betz, 2005 ). Release-ready vesicles are docked against the inside of the presynaptic membrane, ready to release their contents when an action potential arrives. These vesicles constitute less than 1 percent of the total number found in the terminal. Vesicles in the recycling pool constitute 10–15 percent of the total pool of vesicles, and those in the reserve pool make up the remaining 85–90 percent. If the axon fires at a low rate, only vesicles from the release-ready pool will be called on. If the rate of firing increases, vesicles from the recycling pool and finally from the reserve pool will release their contents.

What happens to the membrane of the synaptic vesicles after they have broken open and released the neurotransmitter they contain? It appears that many vesicles in the ready-release pool use a process known as kiss and run. These synaptic vesicles release most or all of their neurotransmitter, the fusion pore closes, and the vesicles break away from the presynaptic membrane and get filled with neurotransmitter again. Other vesicles (primarily those in the recycling pool) merge and recycle and consequently lose their identity. The membranes of these vesicles merge with the presynaptic membrane. Little buds of membrane then pinch off into the cytoplasm and become synaptic vesicles. The appropriate proteins are inserted into the membrane of these vesicles, and the vesicles are filled with molecules of the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. (Endocytosis means “the process of entering a cell.”) Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane. The recycling process takes less than a second for the readily releasable pool, a few seconds for the recycling pool, and a few minutes for the reserve pool. (See Figure 2.32 . )

FIGURE 2.31 Release of Neurotransmitter

These photomicrographs show the release of neurotransmitter by a terminal button that forms a synapse with a frog muscle. The views are of the surface of the fusion zone of the terminal button. (a) Just before release. The two rows of dots are probably calcium channels. (b) During release. The larger circles are holes in the presynaptic membrane, revealing the contents of the synaptic vesicles that have fused with it.

(From Heuser, J., and Reese, T. Journal of Cell Biology, 1981, 88, 564–580. Reprinted with permission.)

FIGURE 2.32 Recycling of the Membrane of Synaptic Vesicles

After synaptic vesicles have released neurotransmitter into the synaptic cleft, the following takes place: In “kiss and run,” the vesicle fuses with the presynaptic membrane, releases the neurotransmitter, reseals, leaves the docking site, becomes refilled with the neurotransmitter, and mixes with other vesicles in the terminal button. In “merge and recycle,” the vesicle completely fuses with the postsynaptic membrane, losing its identity. Extra membrane from fused vesicles pinches off into the cytoplasm and forms vesicles, which are filled with the neurotransmitter. The membranes of vesicles in the reserve pool are recycled through a process of bulk endocytosis. Large pieces of the membrane of the terminal button fold inward, break off, and enter the cytoplasm. New vesicles are formed from small buds that break off of these pieces of membrane.

Activation of Receptors

How do molecules of the neurotransmitter produce a depolarization or hyperpolarization in the postsynaptic membrane? They do so by diffusing across the synaptic cleft and attaching to the binding sites of special protein molecules located in the postsynaptic membrane, called postsynaptic receptors . Once binding occurs, the postsynaptic receptors open neurotransmitter-dependent ion channels , which permit the passage of specific ions into or out of the cell. Thus, the presence of the neurotransmitter in the synaptic cleft allows particular ions to pass through the membrane, changing the local membrane potential.

postsynaptic receptor A receptor molecule in the postsynaptic membrane of a synapse that contains a binding site for a neurotransmitter.

neurotransmitter-dependent ion channel An ion channel that opens when a molecule of a neurotransmitter binds with a postsynaptic receptor.

Neurotransmitters open ion channels by at least two different methods, direct and indirect. The direct method is simpler, so I will describe it first. Figure 2.33 illustrates a neurotransmitter-dependent ion channel that is equipped with its own binding site. When a molecule of the appropriate neurotransmitter attaches to it, the ion channel opens. The formal name for this combination receptor/ion channel is an ionotropic receptor . (See Figure 2.33 . )

ionotropic receptor (eye on oh trow pik) A receptor that contains a binding site for a neurotransmitter and an ion channel that opens when a molecule of the neurotransmitter attaches to the binding site.

FIGURE 2.33 Ionotropic Receptors

The ion channel opens when a molecule of neurotransmitter attaches to the binding site. For purposes of clarity the drawing is schematic; molecules of neurotransmitter are actually much larger than individual ions.

Ionotropic receptors were first discovered in the organ that produces electrical current in Torpedo, the electric ray, where they occur in great number. (The electric ray is a fish that generates a powerful electrical current, not some kind of Star Wars weapon.) These receptors, which are sensitive to a neurotransmitter called acetylcholine, contain sodium channels. When these channels are open, sodium ions enter the cell and depolarize the membrane.

The indirect method is more complicated. Some receptors do not open ion channels directly but instead start a chain of chemical events. These receptors are called metabotropic receptors because they involve steps that require that the cell expend metabolic energy. Metabotropic receptors are located in close proximity to another protein attached to the membrane—a G protein . When a molecule of the neurotransmitter binds with the receptor, the receptor activates a G protein situated inside the membrane next to the receptor. When activated, the G protein activates an enzyme that stimulates the production of a chemical called a second messenger . (The neurotransmitter is the first messenger.) Molecules of the second messenger travel through the cytoplasm, attach themselves to nearby ion channels, and cause them to open. Compared with postsynaptic potentials produced by ionotropic receptors, those produced by metabotropic receptors take longer to begin and last longer. (See Figure 2.34 . )

metabotropic receptor (meh tab oh trow pik ) A receptor that contains a binding site for a neurotransmitter; activates an enzyme that begins a series of events that opens an ion channel elsewhere in the membrane of the cell when a molecule of the neurotransmitter attaches to the binding site.

G protein A protein coupled to a metabotropic receptor; conveys messages to other molecules when a ligand binds with and activates the receptor.

second messenger A chemical produced when a G protein activates an enzyme; carries a signal that results in the opening of the ion channel or causes other events to occur in the cell.

The first second messenger to be discovered was cyclic AMP, a chemical that is synthesized from ATP. Since then, several other second messengers have been discovered. As you will see in later chapters, second messengers play an important role in both synaptic and nonsynaptic communication. And they can do more than open ion channels. For example, they can travel to the nucleus or other regions of the neuron and initiate biochemical changes that affect the functions of the cell. They can even turn specific genes on or off, thus initiating or terminating production of particular proteins.

FIGURE 2.34 Metabotropic Receptors

When a molecule of neurotransmitter binds with a receptor, a G protein activates an enzyme, which produces a second messenger (represented by black arrows) that opens nearby ion channels.

Postsynaptic Potentials

As I mentioned earlier, postsynaptic potentials can be either depolarizing (excitatory) or hyperpolarizing (inhibitory). What determines the nature of the postsynaptic potential at a particular synapse is not the neurotransmitter itself. Instead, it is determined by the characteristics of the postsynaptic receptors—in particular, by the particular type of ion channel they open.

As Figure 2.35 shows, four major types of neurotransmitter-dependent ion channels are found in the postsynaptic membrane: sodium (Na+), potassium (K+), chloride (Cl−), and calcium (Ca2+). Although the figure depicts only directly activated (ionotropic) ion channels, you should realize that many ion channels are activated indirectly, by metabotropic receptors coupled to G proteins.

The neurotransmitter-dependent sodium channel is the most important source of excitatory postsynaptic potentials. As we saw, sodium–potassium transporters keep sodium outside the cell, waiting for the forces of diffusion and electrostatic pressure to push it in. Obviously, when sodium channels are opened, the result is a depolarization—an excitatory postsynaptic potential (EPSP) . (See Figure 2.35a . ) We also saw that sodium–potassium transporters maintain a small surplus of potassium ions inside the cell. If potassium channels open, some of these cations will follow this gradient and leave the cell. Because K+ is positively charged, its efflux will hyperpolarize the membrane, producing an inhibitory postsynaptic potential (IPSP). (See Figure 2.35b . ) At many synapses, inhibitory neurotransmitters open the chloride channels, instead of (or in addition to) potassium channels. The effect of opening chloride channels depends on the membrane potential of the neuron. If the membrane is at the resting potential, nothing happens, because (as we saw earlier) the forces of diffusion and electrostatic pressure balance perfectly for the chloride ion. However, if the membrane potential has already been depolarized by the activity of excitatory synapses located nearby, then the opening of chloride channels will permit Cl− to enter the cell. The influx of anions will bring the membrane potential back to its normal resting condition. Thus, the opening of chloride channels serves to neutralize EPSPs. (See Figure 2.35c . )

excitatory postsynaptic potential (EPSP) An excitatory depolarization of the postsynaptic membrane of a synapse caused by the liberation of a neurotransmitter by the terminal button.

inhibitory postsynaptic potential (IPSP) An inhibitory hyperpolarization of the postsynaptic membrane of a synapse caused by the liberation of a neurotransmitter by the terminal button.

FIGURE 2.35 Ionic Movements During Postsynaptic Potentials

The fourth type of neurotransmitter-dependent ion channel is the calcium channel. Calcium ions (Ca2+), being positively charged and being located in highest concentration outside the cell, act like sodium ions; that is, the opening of calcium channels depolarizes the membrane, producing EPSPs. But calcium does even more. As we saw earlier in this chapter, the entry of calcium into the terminal button triggers the migration of synaptic vesicles and the release of the neurotransmitter. In the dendrites of the postsynaptic cell, calcium binds with and activates special enzymes. These enzymes have a variety of effects, including the production of biochemical and structural changes in the postsynaptic neuron. As we will see in Chapter 13 , one of the ways in which learning affects the connections between neurons involves changes in dendritic spines initiated by the opening of calcium channels. (See Figure 2.35d . )

Termination of Postsynaptic Potentials

Postsynaptic potentials are brief depolarizations or hyperpolarizations caused by the activation of postsynaptic receptors with molecules of a neurotransmitter. They are kept brief by two mechanisms: reuptake and enzymatic deactivation.

The postsynaptic potentials produced by most neurotransmitters are terminated by reuptake . This process is simply an extremely rapid removal of neurotransmitter from the synaptic cleft by the terminal button. The neurotransmitter does not return in the vesicles that get pinched off the membrane of the terminal button. Instead, the membrane contains special transporter molecules that draw on the cell’s energy reserves to force molecules of the neurotransmitter from the synaptic cleft directly into the cytoplasm—just as sodium–potassium transporters move Na+ and K+ across the membrane. When an action potential arrives, the terminal button releases a small amount of neurotransmitter into the synaptic cleft and then takes it back, giving the postsynaptic receptors only a brief exposure to the neurotransmitter. (See Figure 2.36 . )

reuptake The reentry of a neurotransmitter just liberated by a terminal button back through its membrane, thus terminating the postsynaptic potential.

Enzymatic deactivation is accomplished by an enzyme that destroys molecules of the neurotransmitter. Postsynaptic potentials are terminated in this way for acetylcholine (ACh) and for neurotransmitters that consist of peptide molecules. Transmission at synapses on muscle fibers and at some synapses between neurons in the central nervous system is mediated by ACh. Postsynaptic potentials produced by ACh are short lived because the postsynaptic membrane at these synapses contains an enzyme called acetylcholinesterase (AChE) . AChE destroys ACh by cleaving it into its constituents: choline and acetate. Because neither of these substances is capable of activating postsynaptic receptors, the postsynaptic potential is terminated once the molecules of ACh are broken apart. AChE is an extremely energetic destroyer of ACh; one molecule of AChE will chop apart more that 5000 molecules of ACh each second.

enzymatic deactivation The destruction of a neurotransmitter by an enzyme after its release—for example, the destruction of acetylcholine by acetylcholinesterase.

acetylcholine (ACh) (a see tul koh leen) A neurotransmitter found in the brain, spinal cord, and parts of the peripheral nervous system; responsible for muscular contraction.

acetylcholinesterase (AChE) (a see tul koh lin ess ter ace) The enzyme that destroys acetylcholine soon after it is liberated by the terminal buttons, thus terminating the postsynaptic potential.

FIGURE 2.36 Reuptake

Molecules of a neurotransmitter that has been released into the synaptic cleft are transported back into the terminal button.

You will recall that Kathryn, the woman featured in the case history that opened this chapter, suffered from progressive muscular weakness. As her neurologist discovered, Kathryn had myasthenia gravis. This disease was first described in 1672 by Thomas Willis, an English physician. The term literally means “grave muscle weakness.” It is not a very common disorder, but most experts believe that many mild cases go undiagnosed.

In 1934, Dr. Mary Walker remarked that the symptoms of myasthenia gravis resembled the effects of curare, a poison that blocks neural transmission at the synapses on muscles. A drug called physostigmine, which deactivates acetylcholinesterase, serves as an antidote for curare poisoning. As we just saw, AChE is an enzyme that destroys the ACh and terminates the postsynaptic potentials it produces. By deactivating AChE, physostigmine greatly increases and prolongs the effects of ACh on the postsynaptic membrane. Thus, it increases the strength of synaptic transmission at the synapses on muscles and reverses the effects of curare. ( Chapter 4 will say more about both curare and physostigmine.)

Dr. Walker reasoned that if physostigmine reversed the effects of curare poisoning, perhaps it would also reverse the symptoms of myasthenia gravis. She tried it, and it did within a matter of a few minutes. Later, pharmaceutical companies discovered drugs that could be taken orally and that produced longer-lasting effects. Nowadays, an injectable drug is used to make the diagnosis (as in Kathryn’s case), and an oral drug is used to treat it. Unfortunately, no cure has yet been found for myasthenia gravis.

Like multiple sclerosis, myasthenia gravis is an autoimmune disease. For some reason the immune system becomes sensitized against the protein that makes up acetylcholine receptors. Almost as fast as new ACh receptors are produced, the immune system destroys them.

Effects of Postsynaptic Potentials: Neural Integration

We have seen how neurons are interconnected by means of synapses, how action potentials trigger the release of neurotransmitters, and how these chemicals initiate excitatory or inhibitory postsynaptic potentials. Excitatory postsynaptic potentials increase the likelihood that the postsynaptic neuron will fire; inhibitory postsynaptic potentials decrease this likelihood. (Remember, “firing” refers to the occurrence of an action potential.) Thus, the rate at which an axon fires is determined by the relative activity of the excitatory and inhibitory synapses on the soma and dendrites of that cell. If there are no active excitatory synapses or if the activity of inhibitory synapses is particularly high, that rate could be close to zero.

Let us look at the elements of this process. To see an interactive animation of the information presented in the rest of this chapter, Simulate postsynaptic potentials on MyPsychLab.

The interaction of the effects of excitatory and inhibitory synapses on a particular neuron is called neural integration . (Integration means “to make whole,” in the sense of combining two or more functions.) Figure 2.37 illustrates the effects of excitatory and inhibitory synapses on a postsynaptic neuron. The top panel shows what happens when several excitatory synapses become active. The release of the neurotransmitter produces depolarizing EPSPs in the dendrites of the neuron. These EPSPs (represented in red) are then transmitted down the dendrites, across the soma, to the axon hillock located at the base of the axon. If the depolarization is still strong enough when it reaches this point, the axon will fire. (See Figure 2.37a . )

neural integration The process by which inhibitory and excitatory postsynaptic potentials summate and control the rate of firing of a neuron.

Now let’s consider what would happen if, at the same time, inhibitory synapses also become active. Inhibitory postsynaptic potentials are hyperpolarizing—they bring the membrane potential away from the threshold of excitation. Thus, they tend to cancel the effects of excitatory postsynaptic potentials. (See Figure 2.37b . )

The rate at which a neuron fires is controlled by the relative activity of the excitatory and inhibitory synapses on its dendrites and soma. If the activity of excitatory synapses goes up, the rate of firing will go up. If the activity of inhibitory synapses goes up, the rate of firing will go down.

Note that neural inhibition (that is, an inhibitory postsynaptic potential) does not always produce behavioral inhibition. For example, suppose a group of neurons inhibits a particular movement. If these neurons are inhibited, they will no longer suppress the behavior. Thus, inhibition of the inhibitory neurons makes the behavior more likely to occur. Of course, the same is true for neural excitation. Excitation of neurons that inhibit a behavior suppresses that behavior. For example, when we are dreaming, a particular set of inhibitory neurons in the brain becomes active and prevents us from getting up and acting out our dreams. (As we will see in Chapter 9 , if these neurons are damaged, people will act out their dreams.) Neurons are elements in complex circuits; without knowing the details of these circuits, one cannot predict the effects of the excitation or inhibition of one set of neurons on an organism’s behavior.

Autoreceptors

Postsynaptic receptors detect the presence of a neurotransmitter in the synaptic cleft and initiate excitatory or inhibitory postsynaptic potentials. But the postsynaptic membrane is not the only location of receptors that respond to neurotransmitters. Many neurons also possess receptors that respond to the neurotransmitter that they themselves release, called autoreceptors .

autoreceptor A receptor molecule located on a neuron that responds to the neurotransmitter released by that neuron.

Autoreceptors can be located on the membrane of any part of the cell, but in this discussion we will consider those located on the terminal button. In most cases these autoreceptors do not control ion channels. Thus, when stimulated by a molecule of the neurotransmitter, autoreceptors do not produce changes in the membrane potential of the terminal button. Instead, they regulate internal processes, including the synthesis and release of the neurotransmitter. (As you may have guessed, autoreceptors are metabotropic; the control they exert on these processes is accomplished through G proteins and second messengers.) In most cases the effects of autoreceptor activation are inhibitory; that is, the presence of the neurotransmitter in the extracellular fluid in the vicinity of the neuron causes a decrease in the rate of synthesis or release of the neurotransmitter. Most investigators believe that autoreceptors are part of a regulatory system that controls the amount of neurotransmitter that is released. If too much is released, the autoreceptors inhibit both production and release; if not enough is released, the rates of production and release go up.

FIGURE 2.37 Neural Integration

(a) If several excitatory synapses are active at the same time, the EPSPs they produce (shown in red) summate as they travel toward the axon, and the axon fires. (b) If several inhibitory synapses are active at the same time, the IPSPs they produce (shown in blue) diminish the size of the EPSPs and prevent the axon from firing.

Other Types of Synapses

So far, the discussion of synaptic activity has referred only to the effects of postsynaptic excitation or inhibition. These effects occur at axosomatic or axodendritic synapses. Axoaxonic synapses work differently. Axoaxonic synapses do not contribute directly to neural integration. Instead, they alter the amount of neurotransmitter released by the terminal buttons of the postsynaptic axon. They can produce presynaptic modulation: presynaptic inhibition or presynaptic facilitation.

As you know, the release of a neurotransmitter by a terminal button is initiated by an action potential. Normally, a particular terminal button releases a fixed amount of neurotransmitter each time an action potential arrives. However, the release of neurotransmitter can be modulated by the activity of axoaxonic synapses. If the activity of the axoaxonic synapse decreases the release of the neurotransmitter, the effect is called presynaptic inhibition . If it increases the release, it is called presynaptic facilitation . (See Figure 2.38 . ) By the way, as we will see in Chapter 4 , the active ingredient in marijuana exerts its effects on the brain by binding with presynaptic receptors.

presynaptic inhibition The action of a presynaptic terminal button in an axoaxonic synapse; reduces the amount of neurotransmitter released by the postsynaptic terminal button.

presynaptic facilitation The action of a presynaptic terminal button in an axoaxonic synapse; increases the amount of neurotransmitter released by the postsynaptic terminal button.

Many very small neurons have extremely short processes and apparently lack axons. These neurons form dendrodendritic synapses, or synapses between dendrites. Because these neurons lack long axonal processes, they do not transmit information from place to place within the brain. Most investigators believe that they perform regulatory functions, perhaps helping to organize the activity of groups of neurons. Because these neurons are so small, they are difficult to study; therefore, little is known about their function.

FIGURE 2.38 An Axoaxonic Synapse

The activity of terminal button A can increase or decrease the amount of neurotransmitter released by terminal button B.

Some larger neurons, as well, form dendrodendritic synapses. Some of these synapses are chemical, indicated by the presence of synaptic vesicles in one of the juxtaposed dendrites and a postsynaptic thickening in the membrane of the other. Other synapses are electrical; the membranes meet and almost touch, forming a gap junction . The membranes on both sides of a gap junction contain channels that permit ions to diffuse from one cell to another. Thus, changes in the membrane potential of one neuron induce changes in the membrane of the other. (See Figure 2.39 . ) Although most gap junctions in vertebrate synapses are dendrodendritic, axosomatic and axodendritic gap junctions also occur. Gap junctions are common in invertebrates; their function in the vertebrate nervous system is not known.

gap junction A special junction between cells that permits direct communication by means of electrical coupling.

FIGURE 2.39 A Gap Junction

A gap junction permits direct electrical coupling between the membranes of adjacent neurons.

(From Bennett, M. V. L., and Pappas, G. D. The Journal of Neuroscience, 1983, 3, 748–761. Reprinted with permission.)

Nonsynaptic Chemical Communication

Neurotransmitters are released by terminal buttons of neurons and bind with receptors in the membrane of another cell located a very short distance away. The communication at each synapse is private. Neuromodulators are chemicals released by neurons that travel farther and are dispersed more widely than are neurotransmitters. Most neuromodulators are peptides , chains of amino acids that are linked together by chemical attachments called peptide bonds (hence their name). Neuromodulators are secreted in larger amounts and diffuse for longer distances, modulating the activity of many neurons in a particular part of the brain. For example, neuromodulators affect general behavioral states such as vigilance, fearfulness, and sensitivity to pain. Chapter 4 discusses the most important neurotransmitters and neuromodulators.

neuromodulator A naturally secreted substance that acts like a neurotransmitter except that it is not restricted to the synaptic cleft but diffuses through the extracellular fluid.

peptide A chain of amino acids joined together by peptide bonds. Most neuromodulators, and some hormones, consist of peptide molecules.

Hormones are secreted by cells of endocrine glands (from the Greek endo-, “within,” and krinein, “to secrete”) or by cells located in various organs, such as the stomach, the intestines, the kidneys, and the brain. Cells that secrete hormones release these chemicals into the extracellular fluid. The hormones are then distributed to the rest of the body through the bloodstream. Hormones affect the activity of cells (including neurons) that contain specialized receptors located either on the surface of their membrane or deep within their nuclei. Cells that contain receptors for a particular hormone are referred to as target cells for that hormone; only these cells respond to its presence. Many neurons contain hormone receptors, and hormones are able to affect behavior by stimulating the receptors and changing the activity of these neurons. For example, a sex hormone, testosterone, increases the aggressiveness of most male mammals.

hormone A chemical substance that is released by an endocrine gland that has effects on target cells in other organs.

endocrine gland A gland that liberates its secretions into the extracellular fluid around capillaries and hence into the bloodstream.

target cell The type of cell that is directly affected by a hormone or other chemical signal.

FIGURE 2.40 Action of Steroid Hormones

Steroid hormones affect their target cells by means of specialized receptors in the nucleus. Once a receptor binds with a molecule of a steroid hormone, it causes genetic mechanisms to initiate protein synthesis.

Peptide hormones exert their effects on target cells by stimulating metabotropic receptors located in the membrane. The second messenger that is generated travels to the nucleus of the cell, where it initiates changes in the cell’s physiological processes. Steroid hormones consist of very small fat-soluble molecules. (Steroid derives from the Greek stereos, “solid,” and Latin oleum, “oil.” They are synthesized from cholesterol.) Examples of steroid hormones include the sex hormones secreted by the ovaries and testes and the hormones secreted by the adrenal cortex. Because steroid hormones are soluble in lipids, they pass easily through the cell membrane. They travel to the nucleus, where they attach themselves to receptors located there. The receptors, stimulated by the hormone, then direct the machinery of the cell to alter its protein production. (See Figure 2.40 . )

steroid A chemical of low molecular weight, derived from cholesterol. Steroid hormones affect their target cells by attaching to receptors found within the nucleus.

In the past few years, investigators have discovered the presence of steroid receptors in terminal buttons and around the postsynaptic membrane of some neurons. These steroid receptors influence synaptic transmission, and they do so rapidly. Exactly how they work is still not known.

SECTION SUMMARY: Communication Between Neurons

Synapses consist of junctions between the terminal buttons of one neuron and the membrane, another neuron, a muscle cell, or a gland cell. When an action potential is transmitted down an axon, the terminal buttons at the end release a neurotransmitter, a chemical that produces either depolarizations (EPSPs) or hyperpolarizations (IPSPs) of the postsynaptic membrane. The rate of firing of the axon of the postsynaptic neuron is determined by the relative activity of the excitatory and inhibitory synapses on the membrane of its dendrites and soma—a phenomenon known as neural integration.

Terminal buttons contain synaptic vesicles. Most terminal buttons contain two sizes of vesicles, the smaller of which are found in greatest numbers around the release zone of the presynaptic membrane. When an action potential is transmitted down an axon, the depolarization opens voltage-dependent calcium channels, which permit Ca2+ to enter. The calcium ions bind with the clusters of protein molecules in the membranes of synaptic vesicles that are docked at the release zone. The protein clusters spread apart, causing the vesicles to break open and release the neurotransmitter. Vesicles in the ready release pool briefly “kiss” the inside of the presynaptic membrane, release their contents, and then break away to be refilled. Those in the recycling pool and reserve pool completely fuse with the presynaptic membrane and lose their identity. The membrane contributed by these vesicles pinches off into the cytoplasm and is recycled in the production of new vesicles.

The activation of postsynaptic receptors by molecules of a neurotransmitter causes neurotransmitter-dependent ion channels to open, resulting in postsynaptic potentials. Ionotropic receptors contain ion channels, which are directly opened when a ligand attaches to the binding site. Metabotropic receptors are linked to G proteins, which, when activated, open ion channels—usually by producing a chemical called a second messenger.

The nature of the postsynaptic potential depends on the type of ion channel that is opened by the postsynaptic receptors at a particular synapse. Excitatory postsynaptic potentials occur when Na+ enters the cell. Inhibitory postsynaptic potentials are produced when K+ leaves the cell or Cl− enters it. The entry of Ca2+ produces EPSPs, but, even more important, it activates special enzymes that cause physiological changes in the postsynaptic cell that are involved in learning.

Postsynaptic potentials are normally very brief. They are terminated by two means. Acetylcholine is deactivated by the enzyme acetylcholinesterase, and peptides are deactivated by a variety of enzymes. Molecules of the other neurotransmitters are removed from the synaptic cleft by means of transporters located in the presynaptic membrane. This retrieval process is called reuptake.

The presynaptic membrane, as well as the postsynaptic membrane, contains receptors that detect the presence of a neurotransmitter. Presynaptic receptors, also called autoreceptors, monitor the quantity of neurotransmitter that a neuron releases and, apparently, regulate the amount that is synthesized and released.

Axosomatic and axodendritic synapses are not the only kinds found in the nervous system. Axoaxonic synapses either reduce or enhance the amount of neurotransmitter released by the postsynaptic terminal button, producing presynaptic inhibition or presynaptic facilitation. Dendrodendritic synapses also exist, but their role in neural communication is not yet understood.

Nonsynaptic chemical transmission is similar to synaptic transmission. Peptide neuromodulators and hormones activate metabotropic peptide receptors located in the membrane; their effects are mediated through the production of second messengers. Steroid hormones enter the nucleus, where they bind with receptors that are capable of altering the synthesis of proteins that regulate the cell’s physiological processes. These hormones also bind with receptors located elsewhere in the cell, but less is known about their functions.

■ THOUGHT QUESTION

· 1. Why does synaptic transmission involve the release of chemicals? Direct electrical coupling of neurons is far simpler, so why do our neurons not use it more extensively? (A tiny percentage of synaptic connections in the human brain do use electrical coupling.) Normally, nature uses the simplest means possible to a given end, so there must be some advantages to chemical transmission. What do you think they are?

· 2. Consider the control of the withdrawal reflex illustrated in Figure 2.14 . Could you design a circuit using electrical synapses that would accomplish the same tasks?

Review Questions

Study and Review on MyPsychLab

Name and describe the parts of a neuron and explain their functions.

Describe the supporting cells of the central and peripheral nervous systems and explain the blood–brain barrier.

Briefly describe the role of neural communication in a simple reflex and its inhibition by brain mechanisms.

Describe the measurement of the action potential and explain the dynamic equilibrium that is responsible for the membrane potential.

Describe the role of ion channels in action potentials and explain the all-or-none law and the rate law.

Describe the structure of synapses, the release of the neurotransmitter, and the activation of postsynaptic receptors.

Describe postsynaptic potentials: the ionic movements that cause them, the processes that terminate them, and their integration.

Describe the regulation of the effects of the neurotransmitters by autoreceptors, presynaptic inhibition, presynaptic facilitation, and nonsynaptic communication.

Explore the Virtual Brain in MyPsychLab

■ NEURAL CONDUCTION AND SYNAPTIC TRANSMISSION

For the nervous system to function normally, its parts must communicate among one another. The Neural Conduction and Synaptic Transmission module of the virtual brain depicts the different parts of the nervous system, which communicate by the mechanisms described in this chapter.

Discussion: Use only the modules I will upload which the Author is (Carlson, N. R. (2013). Physiology of behavior. Boston: Pearson). Use them as the reference. Please be careful with grammar and spelling. No Running Head Please.

1.Explain the action potential, including: What events happen to form an action potential? How does the action potential move down the axon? How does the action potential trigger the release of neurotransmitters at the synapse? Why are neurotransmitters important for brain function? Describe how neurotransmitters function in the synapse and brain.200 words

2.Explain the placebo effects and give example.200 words

3. Explain Psychopharmacology and give examples.200 words

4.Explain, elaborate and give examples on Neurotransmitters.200 words

36450 Topic: Discussion 1 Number of Pages: 3 (Double Spaced) Number of sources: 1 Writing Style: APA Type of document: Essay Academic Level:Master Category: Psychology Language Style: English (U.S.) Order Instructions: Please use only the modules chapter 2 and chapter 4 I will upload which the Author is Carlson, N. R. (2013). Physiology of behavior. Boston: Pearson in the essay. on the uploaded documents please also read the instruction provided.

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