Graduate Psychology

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chapter 4 Psychopharmacology

Outline

■ Principles of PsychopharmacologyPrinciples of Psychopharmacology

PharmacokineticsPharmacokinetics

Drug EffectivenessDrug Effectiveness

Effects of Repeated AdministrationEffects of Repeated Administration

Placebo EffectsPlacebo Effects

Section SummarySection Summary

■ Sites of Drug ActionSites of Drug Action

Effects on Production of NeurotransmittersEffects on Production of Neurotransmitters

Effects on Storage and Release of NeurotransmittersEffects on Storage and Release of Neurotransmitters

Effects on ReceptorsEffects on Receptors

Effects on Reuptake or Destruction of NeurotransmittersEffects on Reuptake or Destruction of Neurotransmitters

Section SummarySection Summary

■ Neurotransmitters and NeuromodulatorsNeurotransmitters and Neuromodulators

AcetylcholineAcetylcholine

The MonoaminesThe Monoamines

DopamineDopamine

Amino AcidsAmino Acids

PeptidesPeptides

LipidsLipids

NucleosidesNucleosides

Soluble GasesSoluble Gases

Section SummarySection Summary

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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 2Chapter 2 introduced you to the cells of the nervous system, and Chapter 3Chapter 3 described its basic structure.

Now it is time to build on this information by introducing the field of psychopharmacology.

PsychopharmacologyPsychopharmacology is the study of the effects of drugs on the nervous system and (of course) on

behavior. (Pharmakon is the Greek word for “drug.”)

psychopharmacologypsychopharmacology 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

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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.

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As we will see in this chapter, drugs have effects and sites of action. Drug effectsDrug 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 actionsites 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 effectdrug effect The changes a drug produces in an animal’s physiological processes and behavior.

sites of actionsites 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 16Chapters 16 and 1717 discuss the

use of drugs to study and treat mental disorders such as schizophrenia, depression, and the anxiety

disorders, and Chapter 18Chapter 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 pharmacokineticspharmacokinetics (“movements of drugs”).

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pharmacokineticspharmacokinetics 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)intravenous (IV)

injectioninjection—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) injectionintravenous (IV) injection Injection of a substance directly into a vein.

An intraperitoneal (IP) injectionintraperitoneal (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) injectionintramuscular (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

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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) injectionsubcutaneous (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 (intraperitoneal (IP) injection (in tra pair i toe neenee ul)) Injection of a substance into the peritoneal cavity

—the space that surrounds the stomach, intestines, liver, and other abdominal organs.

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

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

Oral administrationOral 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 administrationSublingual 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 administrationoral administration Administration of a substance into the mouth so that it is swallowed.

sublingual administration (sublingual administration (sub lingling 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 administrationIntrarectal 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 administrationintrarectal administration Administration of a substance into the rectum.

The lungs provide another route for drug administration: inhalationinhalation. 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.

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inhalationinhalation 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 topicaltopical

administrationadministration. 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 administrationtopical 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 2Chapter 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 intracerebralintracerebral

administrationadministration, is described in more detail in Chapter 5Chapter 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) administrationintracerebroventricular (ICV) administration, is used very rarely in humans—primarily to deliver

antibiotics directly to the brain to treat certain types of infections.

intracerebral administrationintracerebral administration Administration of a substance directly into the brain.

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

ventricles.

Figure 4.1Figure 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 4.1Figure 4.1..)

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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.

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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 curvedose-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 4.2Figure 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 4.2Figure 4.2..)

dose-response curvedose-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

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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 4.3Figure 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 4.3Figure 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 indextherapeutic 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 indextherapeutic 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.

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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 affinityaffinity 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.

affinityaffinity 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 tolerancetolerance. In other cases a drug becomes more and more

effective—a phenomenon known as sensitizationsensitization.

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

sensitizationsensitization 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

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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 withdrawalwithdrawal

symptomssymptoms 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 symptomwithdrawal 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 18Chapter 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 placeboplacebo 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 specific

physiological 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.

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placebo (placebo (pla seesee 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.)

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1.

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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 QUESTIONSTHOUGHT 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

antagonistsantagonists. Those that facilitate them are called agonistsagonists. (The Greek word agon means “contest.” Thus,

an agonist is one who takes part in the contest.)

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antagonistantagonist A drug that opposes or inhibits the effects of a particular neurotransmitter on the

postsynaptic cell.

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

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This section will describe the basic effects of drugs on synaptic activity. Recall from Chapter 2Chapter 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 4.4Figure 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 SimulateSimulate actions of drugsactions of drugs on MyPsychLabMyPsychLab, 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 4.4Figure 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 4.4Figure 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.

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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 4.4Figure 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 4.4Figure 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 agonistdirect 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 4.4Figure 4.4..)

direct agonistdirect 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 blockersreceptor blockers or

direct antagonistsdirect antagonists. (See step 7 in Figure 4.4Figure 4.4..)

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

from binding with the receptor.

direct antagonistdirect antagonist A synonym for receptor blocker.

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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 bindingnoncompetitive 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 antagonistindirect antagonist. The ultimate effect of an indirect antagonist is

similar to that of a direct antagonist, but its

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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 agonistindirect agonist. (See Figure 4.5Figure 4.5..)

noncompetitive bindingnoncompetitive binding Binding of a drug to a site on a receptor; does not interfere with the binding

site for the principal ligand.

indirect antagonistindirect 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 agonistindirect 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.

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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 2Chapter 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 4.4Figure 4.4..)

We also saw in Chapter 2Chapter 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 heteroreceptorspresynaptic 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 4.6Figure 4.6..)

presynaptic heteroreceptorpresynaptic 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 2Chapter 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 activate

dendritic 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 4.7Figure 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.

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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 4.4Figure 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

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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 QUESTIONTHOUGHT QUESTION

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

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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 “urur 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

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the medial septum control the electrical rhythms of the hippocampus and modulate its functions, which

include the formation of particular kinds of memories.

Figure 4.8Figure 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 5Chapter 5. (See Figure 4.8Figure 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;

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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-CoAAcetyl-CoA is simply CoA with an acetate

ion attached to it. ACh is produced by the following reaction: In the presence of the enzyme cholinecholine

acetyltransferase (ChAT)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 4.9Figure 4.9..)

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

choline acetyltransferase (ChAT) (choline acetyltransferase (ChAT) (kohkoh leen a see tul transtrans 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.)

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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 toxinBotulinum 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 4.4Figure 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,

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black widow spider venomblack widow spider venom has the opposite effect: It stimulates the release of ACh (step 4 of Figure 4.4Figure 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 (botulinum toxin (bot you linlin um)) An acetylcholine antagonist; prevents release by terminal buttons.

black widow spider venomblack 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 2Chapter 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 4.10Figure 4.10..)

Drugs that deactivate AChE (step 11 of Figure 4.4Figure 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 2Chapter 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 neostigmineneostigmine, 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 (neostigmine (nee o stigstig meen)) A drug that inhibits the activity of acetylcholinesterase.

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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 4.4Figure 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 receptorsnicotinic receptors and muscarinic receptorsmuscarinic receptors, respectively. Because muscle fibers must be able to contract

rapidly, they contain the rapid, ionotropic nicotinic receptors.

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

curare.

muscarinic receptor (muscarinic receptor (muss ka rinrin 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 block

them (step 7 of Figure 4.4Figure 4.4). Both drugs were discovered in nature long ago, and both are still used by

modern medicine. The first, atropineatropine, 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 (atropine (a tro peena tro peen)) A drug that blocks muscarinic acetylcholine receptors.

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CatecholaminesCatecholamines IndolamineIndolamine EthylamineEthylamine

Dopamine Serotonin Histamine

Norepinephrine    

Epinephrine    

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Another drug, curarecurare, 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 (curare (kew rahr eekew 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 monoaminesmonoamines. 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 catecholaminescatecholamines. It is

worthwhile learning the terms in Table 4.1Table 4.1, because they will be used throughout the rest of this book.

(See Table 4.1Table 4.1..)

monoamine (monoamine (mahnmahno a meen)) A class of amines that includes indolamines, such as serotonin; and

catecholamines, such as dopamine, norepinephrine, and epinephrine.

catecholamine (catecholamine (cat a kohlkohl 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

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The first catecholamine in Table 4.1Table 4.1, dopamine (DA)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 8Chapters 8, 99, 1313, 1616, and 1818. 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 LL-DOPA-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 4.11Figure 4.11..

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

LL-DOPA (-DOPA (ell dopedope 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 3.21Figure 3.21; the ventral tegmental area is located just below this region.) The cell bodies of

neurons of the nigrostriatal systemnigrostriatal 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 mesolimbicmesolimbic

systemsystem are located in the ventral tegmental area and project their axons to several parts of the

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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 systemmesocortical 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 4.12Figure 4.12..

nigrostriatal system (nigrostriatal system (nigh grow stry ayay tul)) A system of neurons originating in the substantia nigra and

terminating in the neostriatum (caudate nucleus and putamen).

mesolimbic system (mesolimbic system (mee zo limlim bik)) A system of dopaminergic neurons originating in the ventral

tegmental area and terminating in the nucleus accumbens, amygdala, and hippocampus.

mesocortical system (mesocortical system (mee zo korkor ti kul)) A system of dopaminergic neurons originating in the ventral

tegmental area and terminating in the prefrontal cortex.

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FIGURE 4.11 Biosynthesis of the Catecholamines

Degeneration of dopaminergic neurons that connect the substantia nigra with the caudate nucleus causes

Parkinson’s diseaseParkinson’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 4.4Figure 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.

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Parkinson’s diseaseParkinson’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, AMPTAMPT (or α-methyl-p-tyrosine), inactivates tyrosine hydroxylase, the enzyme that converts

tyrosine to L-DOPA (step 2 of Figure 4.4Figure 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.

AMPTAMPT A drug that blocks the activity of tyrosine hydroxylase and thus interferes with the synthesis of

the catecholamines.

The drug reserpinereserpine prevents the storage of monoamines in synaptic vesicles by blocking the transporters

in the membrane of vesicles of monoaminergic neurons (step 3 of Figure 4.4Figure 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 (reserpine (ree sursur 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: D receptors and D receptors. It appears that D receptors are exclusively postsynaptic,

whereas

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D receptors are found both presynaptically and postsynaptically in the brain. Stimulation of D receptors

increases the production of the second messenger cyclic AMP, whereas stimulation of D receptors

decreases it, as does stimulation of D and D 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 D receptors, but there seem to be some

differences. For example, the drug apomorphineapomorphine is a D agonist, but it seems to have a greater affinity for

presynaptic D receptors than for postsynaptic D 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 D receptors, and the drug begins to act as a

direct agonist. (See Figure 4.13Figure 4.13..)

apomorphine (apomorphine (ap o moremore 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 4.4Figure 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

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

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The production of the catecholamines is regulated by an enzyme called monoamine oxidase (MAO)monoamine oxidase (MAO). This

enzyme is found within monoaminergic terminal buttons, where it destroys excessive amounts of

neurotransmitter.

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A drug called deprenyldeprenyl 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 4.14Figure 4.14..)

monoamine oxidase (MAO) (monoamine oxidase (MAO) (mahnmahn o a meen)) A class of enzymes that destroy the monoamines:

dopamine, norepinephrine, and serotonin.

deprenyl (deprenyl (deppdepp 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 chlorpromazinechlorpromazine, which block D receptors, alleviate these symptoms

(step 7 of Figure 4.4Figure 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 16Chapter 16.

chlorpromazine (chlorpromazine (klor prohproh ma zeen)) A drug that reduces the symptoms of schizophrenia by blocking

dopamine D receptors.

FIGURE 4.14 Role of Monoamine Oxidase

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

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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)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. EpinephrineEpinephrine

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) (norepinephrine (NE) (nor epp i neffneff rin)) One of the catecholamines; a neurotransmitter found in the

brain and in the sympathetic division of the autonomic nervous system.

epinephrine (epinephrine (epp i neffneff 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 4.11Figure 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 4.4Figure 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 acidfusaric acid inhibits the activity of the enzyme dopamine-β-hydroxylase and thus blocks the

production of norepinephrine without affecting the production of dopamine.

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fusaric acid (fusaric acid (few sahrsahr 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

moclobemidemoclobemide specifically blocks MAO-A and hence serves as a noradrenergic agonist.

moclobemide (moclobemide (mok low bembem 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 coeruleuslocus coeruleus, a nucleus located in

the dorsal pons. The axons of these neurons project to the regions shown in Figure 4.15Figure 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 4.15Figure 4.15..)

locus coeruleus (locus coeruleus (sur oooo 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

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branches. Instead, they usually release them through axonal varicositiesaxonal varicosities, beadlike swellings of the axonal

branches. These varicosities give the axonal branches of catecholaminergic neurons the appearance of

beaded chains.

axonal varicosityaxonal 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 noradrenergic

receptors, because they are sensitive to epinephrine (Adrenalin) as well as norepinephrine. Neurons in

the central nervous system contain α - and α -adrenergic receptors and β - and β -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 α type. (The drug idazoxanidazoxan

blocks α autoreceptors and hence acts as an agonist.) All adrenergic receptors are metabotropic, coupled

to G proteins that control the production of second messengers.

idazoxanidazoxan A drug that blocks presynaptic noradrenergic α 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, α receptors produce a slow depolarizing (excitatory) effect

on the postsynaptic membrane, while α 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, α receptors—are also involved in sexual behavior and in the control of appetite.

SEROTONIN

The third monoamine neurotransmitter, serotoninserotonin (also called 5-HT,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) (serotonin (5-HT) (sair a toetoe 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 4.16Figure 4.16..) The drug PCPAPCPA (p-

chlorophenylalanine) blocks the activity of tryptophan hydroxylase and thus serves as a serotonergic

antagonist.

PCPAPCPA 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

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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 FigureFigure

4.174.17..

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-HT . Of these the 5-HT and 5-HT receptors serve as presynaptic autoreceptors. In the

dorsal and median raphe nuclei, 5-HT receptors serve as autoreceptors in the membrane of dendrites

and soma. All 5-HT receptors are metabotropic except for the 5-HT receptor, which is ionotropic. The 5-

HT 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-HT 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.

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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, fluoxetinefluoxetine (Prozac), is used to treat depression, some forms of anxiety

disorders, and obsessive-compulsive disorder. These disorders—and their treatment—are discussed in

Chapters 16Chapters 16 and 1717. Another drug, fenfluraminefenfluramine, 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 12Chapter 12

discusses the topic of obesity and its control by means of drugs.

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

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

Several hallucinogenic drugs produce their effects by interacting with serotonergic transmission. LSDLSD

(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-HT receptors in the forebrain. Another drug, MDMAMDMA

(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.

LSDLSD A drug that stimulates 5-HT receptors.

MDMAMDMA A drug that serves as a noradrenergic and serotonergic agonist, also known as “ecstasy”; has

excitatory and hallucinogenic effects.

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HISTAMINE

HistamineHistamine 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 H receptors are responsible for the itching produced by histamine and for the

constriction of the bronchi seen in asthma attacks, H receptors stimulate gastric secretions, and both H

and H receptors are involved in immune reactions. Cimetidine, an H antagonist, blocks gastric acid

secretion. H receptors serve as autoreceptors on the terminals of histaminergic neurons in the brain;

thus, the drug ciproxifan, an H antagonist, increases the release of histamine. All types of histamine

receptors are found in the central nervous system.

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

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The older antihistamines (H 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 glutamateglutamate (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.

glutamateglutamate 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 receptorNMDA receptor, the AMPAAMPA

receptorreceptor, and the kainate receptorkainate receptor. The other glutamate receptor—the metabotropic glutamate receptormetabotropic 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 receptorNMDA receptor A specialized ionotropic glutamate receptor that controls a calcium channel that is

normally blocked by Mg ions; has several other binding sites.

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

kainate receptor (kainate receptor (kaykay in ate)) An ionotropic glutamate receptor that controls a sodium channel;

stimulated by kainic acid.

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metabotropic glutamate receptor (metabotropic glutamate receptor (meh tab a trohtroh 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 (Ca ) 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 13Chapter 13. The drug AP5 (2-amino-5-AP5 (2-amino-5-

phosphonopentanoate)phosphonopentanoate) blocks the glutamate binding site on the NMDA receptor and impairs synaptic

plasticity and certain forms of learning.

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

receptors.

Figure 4.18Figure 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 4.18Figure 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 (Mg ) 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

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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 4.18Figure 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 (Zn ) 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, PCPPCP (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.

PCPPCP 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 18Chapter 18,

this effect is responsible for the seizures that can be provoked by sudden withdrawal from heavy long-

term alcohol intake.

GABA

GABAGABA (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 allylglycineallylglycine inactivates GAD and

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thus prevents the synthesis of GABA (step 2 of Figure 4.4Figure 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: GABA and GABA . The GABA receptor is ionotropic and controls a chloride

channel; the GABA receptor is metabotropic and controls a potassium channel.

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

allylglycineallylglycine 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, GABA receptors are complex; they contain at least five different binding sites. The

primary binding site is, of course, for GABA. The drug muscimolmuscimol (derived from the ACh agonist

muscarine) serves as a direct agonist for this site (step 6 of Figure 4.4Figure 4.4). Another drug, bicucullinebicuculline, blocks

this GABA binding site, serving as a direct antagonist (step 7 of Figure 4.4Figure 4.4). A second site on the GABA

receptor binds with a class of tranquilizing drugs called the benzodiazepinesbenzodiazepines. 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 GABA receptor. (See Figure 4.19Figure 4.19..)

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

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

benzodiazepine (benzodiazepine (ben zoe dy azzazz a peen)) A category of anxiolytic drugs; an indirect agonist for the

GABA receptor.

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FIGURE 4.19 GABA Receptor

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

Barbiturates, drugs that bind to the steroid site, and benzodiazepines all promote the activity of the

GABA receptor; thus, all these drugs serve as indirect agonists. The benzodiazepines are very effective

anxiolyticsanxiolytics, 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 (anxiolytic (angz ee oh litlit ik)) An anxiety-reducing effect.

Picrotoxin has effects opposite to those of benzodiazepines and barbiturates: It inhibits the activity of the

GABA 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 GABA 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 GABA receptor? This metabotropic receptor, coupled to a G protein, serves as both a

postsynaptic receptor and a presynaptic autoreceptor. A GABA agonist, baclofen, serves as a muscle

relaxant. Another drug, CGP 335348, serves as an antagonist. The activation of GABA receptors opens

potassium channels, producing hyperpolarizing inhibitory postsynaptic potentials.

GLYCINE

The amino acid glycineglycine 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

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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 (glycine (glygly 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 strychninestrychnine, 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 (strychnine (strik neenstrik 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, 19981998; Nicoll and Malenka, 19981998). 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

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of the best known families of peptides is the endogenous opioidsendogenous 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 opiate refers to drugs.) Pert, Snowman, and Snyder (19741974) 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., 19751975; Terenius and Wahlström, 19751975), which they called enkephalinsenkephalins (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 (endogenous opioid (en dodgedodge en us ohoh pee oyd)) A class of peptides secreted by the brain that act as

opiates.

enkephalin (enkephalin (en keffkeff 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 7Chapter 7, and the brain mechanisms of opiate addiction are discussed in Chapter 18Chapter 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 4.4Figure 4.4).

Several opiate receptor blockers have also been developed (step 7 of Figure 4.4Figure 4.4). One of them, naloxonenaloxone, 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 (naloxone (na loxlox own)) A drug that blocks opiate receptors.

As we saw in Chapter 2Chapter 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.

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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 endocannabinoidsendocannabinoids (“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. (19901990) discovered that THCTHC (tetrahydrocannabinol, the

active ingredient of marijuana) stimulates cannabinoid receptors located in specific regions of the brain.

(See Figure 4.20Figure 4.20..) Two types of cannabinoid receptors, CB and CB , both metabotropic, have since been

discovered. CB receptors are found in the brain, especially in the frontal cortex, anterior cingulate cortex,

basal ganglia, cerebellum, hypothalamus, and hippocampus. Very low levels of CB receptors are found in

the brain stem, which accounts for the low toxicity of THC. CB receptors are found outside the brain,

especially in cells of the immune system.

endocannabinoid (endocannabinoid (en do can abab in oyd)) A lipid; an endogenous ligand for cannabinoid receptors,

which also bind with THC, the active ingredient of marijuana.

THCTHC The active ingredient in marijuana; activates CB receptors in the brain.

THC produces analgesia and sedation, stimulates appetite, reduces nausea caused by drugs used to treat

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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. (19921992) discovered the first natural ligand for the THC receptor: a lipidlike substance that they

named anandamideanandamide, from the Sanskrit word ananda, or “bliss.” A few years after the discovery of

anandamide, Mechoulam et al. (19951995) 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 5Chapter 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 (anandamide (a nannan 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, FAAHFAAH (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. CB receptors

are blocked by the drug rimonabantrimonabant, the enzyme FAAH is inhibited by MAFPMAFP, and reuptake is inhibited by

AM1172AM1172.

FAAHFAAH Fatty acid amide hydrolase, the enzyme that destroys anandamide after it is brought back into

the cell by anandamide transporters.

rimonabantrimonabant A drug that blocks CB receptors.

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

AM1172AM1172 A drug that inhibits the reuptake of anandamide.

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CB 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, 20032003). 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 CB 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

CB receptors abolishes the reinforcing effects of morphine but not of cocaine, amphetamine, or nicotine

(Cossu et al., 20012001). These effects of cannabinoids are discussed further in Chapter 18Chapter 18.

I mentioned three paragraphs ago that THC (and, of course, the endocannabinoids) have an analgesic

effect. Agarwal et al. (20072007) found that THC exerts its analgesic effects by stimulating CB 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 CB 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 CB antagonist completely blocks the analgesic effect of acetaminophen

(Bertolini et al., 20062006).

Nucleosides

A nucleoside is a compound that consists of a sugar molecule bound with a purine or pyrimidine base.

One of these compounds, adenosineadenosine (a combination of ribose and adenine), serves as a neuromodulator in

the brain.

adenosine (adenosine (a denden 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.

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ItemItem Caffeine ContentCaffeine Content

ChocolatesChocolates  

Baking chocolate 35 mg/oz

Milk chocolate 6 mg/oz

BeveragesBeverages  

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

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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

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 9Chapter 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, caffeinecaffeine, blocks adenosine receptors (step 7 of Figure 4.4Figure 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 4.2Table 4.2..)

caffeinecaffeine 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)nitric oxide (NO), has received

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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, 19921992).

As we will see in Chapter 13Chapter 13, NO may also play a role in the establishment of neural changes that are

produced by learning.

nitric oxide (NO)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 nitricnitric

oxide synthaseoxide synthase. This enzyme can be inactivated (step 2 of Figure 4.4Figure 4.4) by a drug called L-NAME (nitro-L-

arginine methyl ester).

nitric oxide synthasenitric 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.)

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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. CB receptors are found in the central nervous system, and CB 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 4.3Table 4.3..

■ THOUGHT QUESTIONSTHOUGHT 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

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NeurotransmitterNeurotransmitter Name of DrugName of Drug Effect of DrugEffect of Drug Effect on SynapticEffect on Synaptic TransmissionTransmission

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

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 D receptors

Blocks D receptors

Blocks DA reuptake

Stimulates release of DA

Blocks MAO-B

Agonist

Antagonist

Antagonist

Antagonist

Antagonist

Agonist

Agonist

Agonist

Norepinephrine (NE)

Fusaric acid

Reserpine

Idazoxan

Desipramine

Moclobemide

MDMA, amphetamine

Inhibits synthesis of NE

Inhibits storage of NE in synaptic vesicles

Blocks α autoreceptors

Inhibits reuptake of NE

Inhibits MAO-A

Stimulates release of NE

Antagonist

Antagonist

Agonist

Agonist

Agonist

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-HT receptors

Stimulates release of 5-HT

Antagonist

Antagonist

Agonist

Agonist

Agonist

Agonist

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NeurotransmitterNeurotransmitter Name of DrugName of Drug Effect of DrugEffect of Drug Effect on SynapticEffect on Synaptic TransmissionTransmission

Histamine Diphenhydramine

Cimetidine

Ciproxifan

Blocks H receptors

Blocks H receptors

Blocks H autoreceptors

Antagonist

Antagonist

Agonist

Glutamate AMPA

Kainic acid

NMDA

AP5

Stimulates AMPA receptor

Stimulates kainate receptor

Stimulates NMDA receptor

Blocks NMDA receptor

Agonist

Agonist

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

Agonist

Agonist

Adenosine Caffeine Blocks adenosine receptors Antagonist

Nitric oxide (NO) L-NAME

Sildenafil

Inhibits synthesis of NO

Inhibits destruction of cyclic GMP

Antagonist

Agonist

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Review Questions

StudyStudy and ReviewReview on MyPsychLabMyPsychLab

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 CIRCUITSDRUG 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 AddictionDrug Addiction

and Brain Reward Circuitsand Brain Reward Circuits module of the virtual brain show these circuits.

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