CONTENTS Preface vii Chapter 1 Principles of Chemical Neurotransmission 1 Chapter 2 Receptors and Enzymes as the Targets of Drug Action 35 Chapter 3 Special Properties of Receptors 77 Chapter 4 Chemical Neurotransmission as the Mediator of Disease Actions 99 Chapter 5 Depression and Bipolar Disorders 135 Chapter 6 Classical Antidepressants, Serotonin Selective Reuptake Inhibitors, and. Noradrenergic Reuptake Inhibitors 199 Chapter 7 Newer Antidepressants and Mood Stabilizers 245 Chapter 8 Anxiolytics and Sedative-Hypnotics 297 Chapter 9 Drug Treatments for Obsessive-Compulsive Disorder, Panic Disorder, and Phobic Disorders 335 xi xii Contens Chapter 10 Psychosis and Schizophrenia 365 Chapter 11 Antipsychotic Agents 401 Chapter 12 Cognitive Enhancers 459 Chapter 13 Psychopharmacology of Reward and Drugs of Abuse 499 Chapter 14 Sex-Specific and Sexual Function-Related Psychopharmacology 539 Suggested Reading 569 Index 575 CME Post Tests and Evaluations CHAPTER 3 SPECIAL PROPERTIES OF RECEPTORS I. Multiple receptor subtypes A. Definition and description B. Pharmacological subtyping C. Receptor superfamilies II. Agonists and antagonists A. Antagonists B. Inverse agonists C. Partial agonists D. Light and dark as an analogy for partial agonists III. Allosteric modulation A. Positive allosteric interactions B. Negative allosteric interactions IV. Co-transmission versus allosteric modulation V. Summary The study of receptor psychopharmacology involves understanding not only that receptors are the targets for most of the known drugs but also that they have some very special properties. This chapter will build on the discussion of the general properties of receptors introduced in Chapter 2 and will introduce the reader to some of the special properties of receptors that help explain how they participate in key drug interactions. Specifically, we will discuss three important psychopharma- cological principles of receptors: first, that they are organized into multiple subtypes; second, that their interactions with drugs can define not only agonists and antagonists but also partial agonists and inverse agonists; and finally, that allosteric modulation is an important theme of receptor modulation by drugs. 77 78 Essential Psychopharmacology Multiple Receptor Subtypes Definition and Description There are at least two ways to categorize receptors. One is based on describing all the receptors that share a common neurotransmitter. This is sometimes called pharmacological subtyping. The other organizational scheme for receptors is to classify them according to their common structural features and molecular interactions, a classification sometimes called receptor superfamilies. Additional classification schemes will not be discussed here in any detail but include those with related gene and/or chromosome localizations and those with the same effector systems, (e.g., stimulatory or inhibitory G proteins or sodium, potassium, chloride, or calcium channels). These features of different receptors will be discussed as specific neurotransmitter receptors are mentioned throughout the rest of the book. Pharmacological Subtyping To increase the options for brain communication, each neurotransmitter can act on more than one neurotransmitter receptor. That is, there is not a single acetylcholine receptor, nor a single serotonin receptor, nor a single norepinephrine receptor. In fact, multiple subtypes have been discovered for virtually every known neurotransmitter receptor. It is as though the neurotransmitter keys in the brain can open many receptor locks. Thus, the neurotransmitter is the master key. Whereas some drugs act like duplicates of master keys, others can be made more selective and act at only one of the receptors, like a submaster key for a single lock (Fig. 3 — 1). This makes for clever engineering of the communications that occur via the brain's neurotransmitters and receptors. Because the system of chemical neurotransmission uses multiple neurotransmitters, each working through multiple receptors, chemical signaling provides the features of both selectivity and amplification. That is, while there is selectivity of a receptor family for a single neurotransmitter, there is nevertheless amplification of receptor communication due to the presence of a great variety of neurotransmitter receptors for the same neurotransmitter. Thus, each neurotransmitter has not only the property of selectivity when compared with other neurotransmitters but also a redundancy of receptor subtypes sharing the same neurotransmitter. Receptor subtypes allow a single neurotransmitter to perform quite different functions, depending not only on which particular subtype it is binding but also on where in the brain's topography any receptor subtype is localized. Receptor Superfamilies There are two major superfamilies of receptors. The first is the superfamily of which all members have seven transmembrane regions, all use a G protein, and all use a second-messenger system (represented as an icon in Fig. 3—2). This was extensively discussed in the text and figures of Chapter 2. Individual member receptors within this class may, however, use various different neurotransmitters and still be a member of this same superfamily. What makes one member of the family use one neuro- Special Properties of Receptors 79 FIGURE 3 — 1. Neurotransmitters have multiple receptor subtypes with which to interact. It is as though the neurotransmitter is the master key capable of unlocking each of the multiple receptor subtype locks. Drugs can be made that mimic the neurotransmitter. The most selective drugs are capable of mimicking the natural neurotransmitter's action at just one of the receptor locks. This figure shows a neurotransmitter capable of interacting with six different receptor subtypes (i.e., the master key). Also shown are six different drugs on a key chain. Each of these drugs is selective for a different single subtype of the neurotransmitter receptors. transmitter and another member of this same family use another neurotransmitter is probably the molecular makeup of that portion of the transmembrane region that binds the neurotransmitter (see Figs. 2 — 3, 2 — 5, and 2 — 6). The molecular configuration of the neurotransmitter binding site differs from one receptor to the next in the same family. This is how different neurotransmitters can be used in the same receptor superfamily. The differences in binding sites between receptors in the same superfamily are generally based on substitution of different amino acids at a few critical places in the receptor's amino acid chain (Fig. 2 — 1). Precise substitution of amino acids in just a few key places can thus transform a receptor with binding characteristics for one neurotransmitter into a receptor with vast changes in its binding characteristics so that it now recognizes and binds an entirely different neurotransmitter. This has been previously discussed in Chapter 2 and represented in earlier figures, including Figures 2 — 1 to 2 — 3. A second superfamily of receptors shares a common molecular makeup in which every member has four transmembrane regions, with five copies of each receptor configured around an ion channel (represented as icons in Figs. 3-3 and 3-4; see 80 Essential Psychopharmacology FIGURE 3 — 2. Represented here is one of the two major superfamilies of neurotransmitter receptors. This superfamily is called the G protein—linked receptor superfamily. Each member of this family has a receptor containing seven transmembrane regions (shown in Figs. 2 — 1 and 2 — 2) but given here as a simple receptor icon. Each receptor in this family is linked to a G protein and also uses a second-messenger system triggered by a cooperating enzyme. A more detailed breakdown and explanation of this superfamily with a series of icons was given in Figures 2 — 25 through 2 — 22. also Figs. 2 — 5 and 2—6). The ion channel may differ from one receptor to another in this superfamily, and the neurotransmitter may also differ from one family member to another. However, all are arranged in a similar molecular form, concentrically around the ion channel. Another common feature of this superfamily is that not only are there multiple copies of each receptor but many different types of receptor are present. Thus, the ion channel is surrounded by multiple copies of many different receptors (Fig. 3 — 3). This allows the critical passage of ions into the cell via the ion channel to be regulated by multiple neurotransmitters and drugs rather than just a single neurotransmitter. It seems that regulating an ion channel is too important a job to be left up to a single neurotransmitter. Thus, the brain has arranged for many different gatekeepers to watch over the passage of ions into the neuron. Sometimes the various gatekeepers that have a say in the regulation of the channel compete with each other to neutralize each other. Sometimes they cooperate to boost each other's actions. There may even be two neurotransmitters that can be active at such receptors; these are known then as co-transmitters. The ion channel itself is essentially a column of columns. By binding to the binding sites in the receptor columns, the neurotransmitter causes the opening and closing of the ion channel column in the center of all the columns (i.e., within the Special Properties of Receptors 81 FIGURE 3 — 3. The second major superfamily of neurotransmitter receptors is represented here. This superfamily is called the ligand-gated ion channel receptors. This receptor has