Psychopharmacology Principles PDF

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 we...

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 C hapter 2 introduced you to the cells of the nervous system, and Chapter 3 described its basic structure. Now it is time to build on this information by introducing the field of psychopharmacology. Psychopharmacology is the study of the effects of drugs on the nervous system and (of course) on behavior. (Pharmakon is the Greek word for “drug.”) 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 psychopharmacology, 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. we will concern ourselves here only with chemicals that alter the functions of cells within the nervous system. The word exogenous rules out chemical messengers produced by the body, such as neurotransmitters, neuromodulators, or hormones. (Exogenous means “produced from without”—that is, from outside the body.) Chemical messengers produced by the body are not drugs, although synthetic chemicals that mimic their effects are classified as drugs. The definition of a drug also rules out essential nutrients, such as proteins, fats, carbohydrates, minerals, and vitamins that are a necessary constituent of a healthy diet. Finally, it states that drugs are effective in low doses. This qualification is important, because large quantities of almost any substance—even common ones such as table salt—will alter the functions of cells. x psychopharmacology The study of the effects of drugs on the nervous system and on behavior. Principles of Psychopharmacology As we will see in this chapter, drugs have effects and sites of action. Drug effects are the changes we can observe in an animal’s physiological processes and behavior. For example, the effects of morphine, heroin, and other opiates include decreased sensitivity to pain, slowing of the digestive system, sedation, muscular relaxation, constriction of the pupils, and euphoria. The sites of action of drugs are the points at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells. For example, the sites of action of the opiates are specialized receptors situated in the membrane of some neurons. When molecules of opiates attach to and activate these receptors, the drugs alter the activity of these neurons and produce their effects. This chapter considers both the effects of drugs and their sites of action. Psychopharmacology is an important field of neuroscience. It has been responsible for the development of psychotherapeutic drugs, which are used to treat psychological and behavioral disorders. It has also provided tools that have enabled other investigators to study the functions of cells of the nervous system and the behaviors controlled by particular neural circuits. This chapter does not contain all this book has to say about the subject of psychopharmacology. Throughout the book you will learn about the use of drugs to investigate the nature of neural circuits involved in the control of perception, memory, and behavior. In addition, Chapters 16 and 17 discuss the use of drugs to study and treat mental disorders such as schizophrenia, depression, and the anxiety disorders, and Chapter 18 discusses the physiology of drug abuse. Principles of Psychopharmacology This chapter begins with a description of the basic principles of psychopharmacology: the routes of administration of drugs and their fate in the body. The second section discusses the sites of drug actions. The final section discusses specific neurotransmitters and neuromodulators and the physiological and behavioral effects of specific drugs that interact with them. Pharmacokinetics To be effective, a drug must reach its sites of action. To do so, molecules of the drug must enter the body and then enter the bloodstream so that they can be carried to the organ (or organs) on which they act. Once there, they must leave the bloodstream and come into contact with the molecules with which they interact. For almost all of the drugs we are interested in, this means that the molecules of the drug must enter the central nervous system (CNS). 101 Some behaviorally active drugs exert their effects on the peripheral nervous system, but these drugs are less important to us than the drugs that affect cells of the CNS. Molecules of drugs must cross several barriers to enter the body and find their way to their sites of action. Some molecules pass through these barriers easily and quickly; others do so very slowly. And once molecules of drugs enter the body, they begin to be metabolized—broken down by enzymes—or excreted in the urine (or both). In time, the molecules either disappear or are transformed into inactive fragments. The process by which drugs are absorbed, distributed within the body, metabolized, and excreted is referred to as pharmacokinetics (“movements of drugs”). ROUTES OF ADMINISTRATION First, let’s consider the routes by which drugs can be administered. For laboratory animals the most common route is injection. The drug is dissolved in a liquid (or, in some cases, suspended in a liquid in the form of fine particles) and injected through a hypodermic needle. The fastest route is intravenous (IV) injection—injection into a vein. The drug enters the bloodstream immediately and reaches the brain within a few seconds. The disadvantages of IV injections are the increased care and skill they require in comparison to most other forms of injection and the fact that the entire dose reaches the bloodstream at once. If an animal is especially sensitive to the drug, there may be little time to administer another drug to counteract its effects. An intraperitoneal (IP) injection is rapid but not as rapid as an IV injection. The drug is injected through the abdominal wall into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs. IP injection is the most common route for administering drugs to small laboratory animals. An intramuscular (IM) injection is made directly into a large muscle, such as those found in the upper arm, thigh, or buttocks. The drug is absorbed into the bloodstream through the capillaries that supply the muscle. If very x drug effect The changes a drug produces in an animal’s physiological processes and behavior. x sites of action The locations at which molecules of drugs interact with molecules located on or in cells of the body, thus affecting some biochemical processes of these cells. x pharmacokinetics The process by which drugs are absorbed, distributed within the body, metabolized, and excreted. x intravenous (IV) injection into a vein. Injection of a substance directly x intraperitoneal (IP) injection (in tra pair i toe nee ul) Injection of a substance into the peritoneal cavity—the space that surrounds the stomach, intestines, liver, and other abdominal organs. x intramuscular (IM) injection muscle. Injection of a substance into a 102 Chapter 4 Psychopharmacology slow absorption is desirable, the drug can be mixed with another drug (such as ephedrine) that constricts blood vessels and retards the flow of blood through the muscle. A drug can also be injected into the space beneath the skin by means of a subcutaneous (SC) injection. A subcutaneous injection is useful only if small amounts of drug need to be administered, because injecting large amounts would be painful. Some fat-soluble drugs can be dissolved in vegetable oil and administered subcutaneously. In this case, molecules of the drug will slowly leave the deposit of oil over a period of several days. If very slow and prolonged absorption of a drug is desirable, the drug can be formed into a dry pellet or placed in a sealed silicone rubber capsule and implanted beneath the skin. Oral administration is the most common form of administering medicinal drugs to humans. Because of the difficulty of getting laboratory animals to eat something that does not taste good to them, researchers seldom use this route. Some chemicals cannot be administered orally because they will be destroyed by stomach acid or digestive enzymes or because they are not absorbed from the digestive system into the bloodstream. For example, insulin, a peptide hormone, must be injected. Sublingual administration of certain drugs can be accomplished by placing them beneath the tongue. The drug is absorbed into the bloodstream by the capillaries that supply the mucous membrane that lines the mouth. (Obviously, this method works only with humans, who will cooperate and leave the capsule beneath their tongue.) Nitroglycerine, a drug that causes blood vessels to dilate, is taken sublingually by people who suffer the pains of angina pectoris, caused by obstructions in the coronary arteries. Drugs can also be administered at the opposite end of the digestive tract, in the form of suppositories. Intrarectal administration is rarely used to give drugs to experimental animals. For obvious reasons this process would be difficult with a small animal. In addition, when agitated, small animals such as rats tend to defecate, which would mean that the drug would not remain in place long enough to be absorbed. And I’m not sure I would want to try to administer a rectal suppository to a large animal. Rectal suppositories are most commonly used to administer drugs that might upset a person’s stomach. The lungs provide another route for drug administration: inhalation. Nicotine, freebase cocaine, and marijuana are usually smoked. In addition, drugs used to treat lung disorders are often inhaled in the form of a vapor or fine mist, and many general anesthetics are gasses that are administered through inhalation. The route from the lungs to the brain is very short, and drugs administered this way have very rapid effects. Some drugs can be absorbed directly through the skin, so they can be given by means of topical administration. Natural or artificial steroid hormones can be administered in this way, as can nicotine (as a treatment to make it easier for a person to stop smoking). The mucous membrane lining the nasal passages also provides a route for topical administration. Commonly abused drugs such as cocaine hydrochloride are often sniffed so that they come into contact with the nasal mucosa. This route delivers the drug to the brain very rapidly. (The technical, rarely used name for this route is insufflation. And note that sniffing is not the same as inhalation; when powdered cocaine is sniffed, it ends up in the mucous membrane of the nasal passages, not in the lungs.) Finally, drugs can be administered directly into the brain. As we saw in Chapter 2, the blood–brain barrier prevents certain chemicals from leaving capillaries and entering the brain. Some drugs cannot cross the blood–brain barrier. If these drugs are to reach the brain, they must be injected directly into the brain or into the cerebrospinal fluid in the brain’s ventricular system. To study the effects of a drug in a specific region of the brain (for example, in a particular nucleus of the hypothalamus), a researcher will inject a very small amount of the drug directly into the brain. This procedure, known as intracerebral administration, is described in more detail in Chapter 5. To achieve a widespread distribution of a drug in the brain, a researcher will get past the blood–brain barrier by injecting the drug into a cerebral ventricle. The drug is then absorbed into the brain tissue, where it can exert its effects. This route, intracerebroventricular (ICV) administration, is used very rarely in humans—primarily to deliver antibiotics directly to the brain to treat certain types of infections. Figure 4.1 shows the time course of blood levels of a commonly abused drug, cocaine, after intravenous injection, inhalation, oral administration, and sniffing. The amounts received were not identical, but the graph illustrates the relative rapidity with which the drug reaches the blood. (See Figure 4.1.) x subcutaneous (SC) injection space beneath the skin. Injection of a substance into the x oral administration Administration of a substance into the mouth so that it is swallowed. x sublingual administration (sub ling wul) Administration of a substance by placing it beneath the tongue. x intrarectal administration the rectum. Administration of a substance into x inhalation Administration of a vaporous substance into the lungs. x topical administration Administration of a substance directly onto the skin or mucous membrane. x intracerebral administration directly into the brain. Administration of a substance x intracerebroventricular (ICV) administration Administration of a substance into one of the cerebral ventricles. x dose-response curve A graph of the magnitude of an effect of a drug as a function of the amount of drug administered. 103 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. 600 500 Intravenous (0.6 mg/kg) 400 Smoked (100 mg base) 300 Oral (2 mg/kg) 200 Intranasal (2 mg/kg) 100 Drug Effectiveness 0 0 60 120 180 240 300 360 420 480 Time (min) FIGURE 4.1 Cocaine in Blood Plasma Carlson/ POB,11e/C11B04F01.eps The graph shows the concentration of cocaine in blood 20.0 x 14.8 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, Drugs vary widely in their effectiveness. The effects of a small dose of a relatively effective drug can equal or exceed the effects of larger amounts of a relatively ineffective drug. The best way to measure the effectiveness of a drug is to plot a dose-response curve. To do this, subjects are given various doses of a drug, usually defined as milligrams of drug per kilogram of a subject’s body weight, and the effects of the drug are plotted. Because the molecules of most drugs distribute themselves throughout the blood and then throughout the rest of the body, a heavier subject (human or laboratory animal) will require a larger quantity of a drug to achieve the same concentration as a smaller quantity will produce in a smaller subject. As Figure 4.2 shows, increasingly stronger doses of a drug cause increasingly larger effects until the point of maximum effect is reached. At this point, increasing the dose of the drug does not produce any more effect. (See Figure 4.2.) 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 high After this point, increasing the dose does not produce a stronger effect Effect of drug Plasma cocaine concentration (ng/ml) Principles of Psychopharmacology low low FIGURE Dose of drug 4.2 A Dose-Response Curve high Carlson/ POB,11e/C11B04F02.eps Increasingly stronger doses of the drug produce 16.7 x 14.2 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. 104 Chapter 4 Dose-response curve for the analgesic effect of morphine Effect of drug high Margin of safety Dose-response curve for the depressive effect of morphine on respiration low low FIGURE Psychopharmacology Dose of drug high 4.3 Dose-Response Curves for Morphine Carlson/ POB,11e/C11B04F03.eps The dose-response curve on the left shows the analgesic 16.6 x 14.6 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. respiration. A physician who prescribes an opiate to relieve a patient’s pain wants to administer a dose that is large enough to produce analgesia but not large enough to depress heart rate and respiration—effects that could be fatal. Figure 4.3 shows two dose-response curves, one for the analgesic effects of a painkiller and one for the drug’s depressant effects on respiration. The difference between these curves indicates the drug’s margin of safety. Obviously, the most desirable drugs have a large margin of safety. (See Figure 4.3.) One measure of a drug’s margin of safety is its therapeutic index. This measure is obtained by administering varying doses of the drug to a group of laboratory animals such as mice. Two numbers are obtained: the dose that produces the desired effects in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. The therapeutic index is the ratio of these two numbers. For example, if the toxic dose is five times higher than the effective dose, then the therapeutic index is 5.0. The lower the therapeutic index, the more care must be taken in prescribing the drug. For example, barbiturates have relatively low therapeutic indexes— as low as 2 or 3. In contrast, tranquilizers such as Valium have therapeutic indexes of well over 100. As a consequence, an accidental overdose of a barbiturate is much more likely to have tragic effects than a similar overdose of Valium. Why do drugs vary in their effectiveness? There are two reasons. First, different drugs—even those with the same behavioral effects—may have different sites of action. For example, both morphine and aspirin have analgesic effects, but morphine suppresses the activity of neurons in the spinal cord and brain that are involved in pain perception, whereas aspirin reduces the production of a chemical involved in transmitting information from damaged tissue to pain-sensitive neurons. Because the drugs act very differently, a given dose of morphine (expressed in terms of milligrams of drug per kilogram of body weight) produces much more pain reduction than the same dose of aspirin does. The second reason that drugs vary in their effectiveness has to do with the affinity of the drug with its site of action. As we will see in the next major section of this chapter, most drugs of interest to psychopharmacologists exert their effects by binding with other molecules located in the central nervous system—with presynaptic or postsynaptic receptors, with transporter molecules, or with enzymes involved in the production or deactivation of neurotransmitters. Drugs vary widely in their affinity for the molecules to which they attach—the readiness with which the two molecules join together. A drug with a high affinity will produce effects at a relatively low concentration, whereas a drug with a low affinity must be administered in higher doses. Thus, even two drugs with identical sites of action can vary widely in their effectiveness if they have different affinities for their binding sites. In addition, because most drugs have multiple effects, a drug can have high affinities for some of its sites of action and low affinities for others. The most desirable drug has a high affinity for sites of action that produce therapeutic effects and a low affinity for sites of action that produce toxic side effects. One of the goals of research by drug companies is to find chemicals with just this pattern of effects. Effects of Repeated Administration Often, when a drug is administered repeatedly, its effects will not remain constant. In most cases its effects will diminish—a phenomenon known as tolerance. In other cases a drug becomes more and more effective—a phenomenon known as sensitization. Let’s consider tolerance first. Tolerance is seen in many drugs that are commonly abused. For example, a x therapeutic index The ratio between the dose that produces the desired effect in 50 percent of the animals and the dose that produces toxic effects in 50 percent of the animals. x affinity The readiness with which two molecules join together. x tolerance A decrease in the effectiveness of a drug that is administered repeatedly. x sensitization An increase in the effectiveness of a drug that is administered repeatedly.