Until now, all the chapters of this book have addressed how psychotropic drugs affect

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1 CHAPTER 19 Disorders of Reward, and Thei r Treatment Drug Abuse, III Reward circuits!ill Nicotine III Alcohol III Opiates II Stimulants III Sedative hypnotics III Marijuana III Hallucinogens III Club drugs III Sexual disorders Sexual disorders and reward II1IIEating disorders III Other impulse-control disorders III Summary Until now, all the chapters of this book have addressed how psychotropic drugs affect Psychopharmacology the brain for therapeutic is generally purposes. defined Unfortunately, as the studypsychotropic of drugs thatdrugs affectcan thealso brain. be abused, and this has caused major public health problems throughout the world. Here we will attempt to explain how abuse of psychotropic agents affects the brain. Our approach to this problem is to discuss how non therapeutic use, short-term abuse (intoxication), and the complications of long-term abuse affect chemical neurotransmission, particularly within reward circuits. We will also discuss the mechanism of action of agents that are now used to treat various substance abuse disorders. Also covered briefly in this chapter are several other disorders thought to be regulated by reward circuitry, including sexual disorders, eating disorders, and various impulse disorders such as gambling. Reward circuitry has a prominent role in most psychiatric disorders, not just in drug abuse. Indeed, links to the reward circuitry can be seen not only for disorders of impulsivity such as attention deficit hyperactivity disorder (ADHD) (discussed in Disorders of Reward, Drug Abuse, and Their Treatment I 943

2 TABLE 19-1 Paradigm-shiftingquestionsforthe moderntreatment of substance abuse 1. Do you have to be an addict in recovery yourself to treat patients with addiction? 2. Is total abstinence the only desirable goal or is reduction in heavy use a valuable stepping stone to recovery? 3. Can drugs be used to treat drug abuse or are they really crutches? Chapter 17), bipolar mania (discussed in Chapters 11 and 13), and anxiety disorders such as obsessive compulsive disorder (OCD) (discussed in Chapter 14), but also for disorders of motivation, such as major depression (discussed in Chapters 11 and 12), apathy in dementia (discussed in Chapter 18) and in schizophrenia (discussed in Chapters 9 and 10), use and abuse of pain medications in chronic pain syndromes (discussed in Chapter 15), and use and abuse of stimulants and sedative hypnotics in sleep/wake disorders (discussed in Chapter 16). In many ways, therefore, abnormalities in the adequate functioning of reward circuitry are key aspects to all the disorders discussed in this text. For that reason, we will discuss what is known about reward circuits in some detail. New treatments for disorders of reward circuitry are finally entering psychopharmacology and the prospects for future therapeutics that target malfunctioning in this circuitry have never been greater. So far, psychopharmacologists have been reluctant to embrace new therapeutics for substance abuse, and thus the uptake of new treatments into clinical practice is often slow and many new treatments are still used minimally by many clinicians. Perhaps the lack of effective psychopharmacological treatments until relatively recently has allowed the field to develop therapeutic nihilism to psychopharmacological approaches. Even today, available psychopharmacological treatments for substance abuse remain few and limited in efficacy, as we shall see in this chapter. However, the time might be right for some paradigm-shifting questions to be posed for the field of substance abuse treatment in the modern era (Table 19-1). For example, should professional psychopharmacologists be first-line treaters of substance abuse, or should this be left predominantly to lay counselors and professionals who have triumphed over their own past substance abuse? Since some treatments may blunt rather than stop all drug abuse behavior, particularly at the initiation of treatment, this leads one to ask: Is total abstinence the only desirable goal of treatment? Finally, is it rational to use drugs to treat drug abuse, or should drugs be seen mostly as crutches to be avoided? Answers to these questions may determine whether more psychopharmacological practitioners become proactive in identifying and treating nicotine addiction; whether more practitioners start to use treatments for heavy drinking and alcoholism, including those that assure compliance for a month but are rarely used; whether more practitioners start to use opiate partial agonists for "middle class" patients dependent upon opiates who have never taken methadone. Perhaps the psychopharmacology of substance abuse and related disorders of reward is poised at the beginning of a new era, analogous to where psychopharmacology stood for the treatment of depression and psychosis in the 1950s, with major new therapeutics just around the corner. At this point, understanding of the neuroscientific basis of reward circuitry and the pharmacological mechanism of action of substances of abuse and their drug treatments is exploding. What is known about this exciting field is summarized and reviewed briefly in this chapter. Mastering this will empower the modern psychopharmacologist to make decisions about whether to enter this field of new therapeutics. 944 I EssentialPsychopharmacology

3 TABLE 19-2 Nine key terms and their definitions ABUSE: Self-administration of any drug in a culturally disapproved manner that causes adverse consequences ADDICTION: A behavioral pattern of drug abuse characterized by overwhelming involvement with the use of a drug (compulsive use), the securing of its supply, and a strong tendency to relapse after discontinuation DEPENDENCE: The physiological state of neuroadaptation produced by repeated administration of a drug, necessitating continued administration to prevent the appearance of the withdrawal syndrome REINFORCEMENT: The tendency of a pleasure-producing drug to lead to repeated self-administration TOLERANCE: Tolerance has developed when after repeated administration, a given dose of a drug produces a decreased effect, or, conversely, when increasingly larger doses must be administered to obtain the effects observed with the original use CROSS-TOLERANCE AND CROSS-DEPENDENCE: The ability of one drug to suppress the manifestations of physical dependence produced by another drug and to maintain the physically dependent state WITHDRAWAL: The psychologic and physiologic reactions to abrupt cessation of a dependence-producing drug RELAPSE: The recurrence, upon discontinuation of an effective medical treatment, of the original condition from which the patient suffered REBOUND: The exaggerated expression of the original condition sometimes experienced by patients immediately after cessation of an effective treatment The goal of this chapter is to provide the biological background that will enable the reader to understand not only how substance abuse is thought to alter reward circuitry but also how currently available treatments for various substance abuse disorders work, including the rationale for current research efforts to discover truly novel and highly effective new treatments for these common and very debilitating illnesses. This chapter therefore provides only a very brief overview of the various substance abuse disorders. Full clinical descriptions and formal criteria for how to diagnose the numerous known diagnostic entities should be obtained by consulting standard reference sources. Some useful definitions of key terms used in this field are given in Table The discussion here emphasizes the links between various pathological mechanisms, brain circuits, and neurotransmitters with the various symptoms of substance abuse, from nicotine to alcohol to opiates to stimulants. Brief mention is made of other drugs of abuse and other impulse disorders that do not involve drugs. Finally, a discussion of various types of sexual dysfunction that are hypothetically linked to reward circuitry is included. Reward circuits The mesolimbic dopamine circuit as the final common pathway of reward The final common pathway of reinforcement and reward in the brain is hypothesized to be the mesolimbic dopamine pathway (Figure 19-1). Some even consider this to be the "pleasure center" of the brain and dopamine to be the "pleasure neurotransmitter." There are many natural ways to trigger your mesolimbic dopamine neurons to release dopamine, ranging from intellectual accomplishments, to athletic accomplishments, to enjoying a good symphony, to experiencing an orgasm. These are sometimes called "natural highs" (Figure 19-1). The inputs to the mesolimbic pathway that mediate these natural highs include a Disorders of Reward, Drug Abuse, and Their Treatment I 945

4 ReWgrq; PA mesqliml)ic;; pathway FIGURE 19-1 The final common pathway of reward. The mesolimbicdopaminepathwaymediatesthe psychopharmacologyof reward,whetherthat is a naturalhighor a drug-inducedhigh, and is sometimesreferred to as the pleasurecenter of the brain,with dopamineas the pleasureneurotransmitter. most incredible "pharmacy" of naturally occurring substances ranging from the brain's own morphine/heroin (endorphins), to the brain's own marijuana (anandamide), to the brain's own nicotine (acetylcholine), to the brain's own cocaine and amphetamine (dopamine itself) (Figure 19-2). The numerous psychotropic drugs of abuse also have a final common pathway of causing the mesolimbic pathway to release dopamine, often in a manner more explosive and pleasurable than that which occurs naturally. These drugs bypass the brain's own neurotransmitters and directly stimulate the brain's own receptors for these drugs, causing dopamine to be released. Since the brain already uses neurotransmitters that resemble drugs of abuse, it is not necessary to earn your reward naturally, since you can get a much more intense reward in the short run and upon demand from a drug of abuse than you can from a natural high with the brain's natural system. However, unlike a natural high, a drug-induced reward causes such wonderful feeding of dopamine to postsynaptic limbic dopamine receptors that they furiously crave even more drug to replenish dopamine once the drug stops working, leading one to be preoccupied with finding drug and thus beginning a vicious cycle of abuse, addiction, dependence, and withdrawal. The reactive reward system: reward from the bottom up Addicts act impulsively, automatically, and obligatorily to cues that lead them to seek and ingest more drug. That is the power of the reactive reward system, which functions 946 I EssentialPsychopharmacology

5 Neurotransmitter?~ Regulation of Mesolimbic Reward nucleus accumbens raphe VTA cannabinoid \ '---"'g\u GP1eA r cannabinoid FIGURE 19-2 Neurotransmitter regulation of mesolimbic reward. The final common pathway of reward in the brain is hypothesized to be the mesolimbic dopamine pathway. This pathway is modulated by many naturally occurring substances in the brain in order to deliver normal reinforcement to adaptive behaviors (such as eating, drinking, sex) and thus to produce "natural highs," such as feelings of joy or accomplishment. These neurotransmitter inputs to the reward system include the brain's own morphine/heroin (i.e., endorphins such as enkephalinj, the brain's own cannabis/marijuana (i.e., anandamidej, the brain's own nicotine (i.e., acetylcholine), and the brain's own cocaine/amphetamine (i.e., dopamine itself), among others. The numerous psychotropic drugs of abuse that occur in nature bypass the brain's own neurotransmitters and directly stimulate the brain's receptors in the reward system, causing dopamine release and a consequent "artificial high." Thus alcohol, opiates, stimulants, marijuana, benzodiazepines, sedative hypnotics, hallucinogens, and nicotine all affect this mesolimbic dopaminergic system. to signal the immediate prospects of either pain or pleasure (Figure 19-3). The reactive reward system provides motivation and behavioral drive from the "bottom up," including not only the ascending mesolimbic dopamine (DA) pathway (shown in Figures 19-1 and 19-2) but also the amygdala and its projections to both ends of the mesolimbic pathway (Figure 19-3). Shown in Figure 19-3 are the connections the amygdala makes both with DA cell bodies in the ventral tegmental area (VTA) and with spiny neurons in the nucleus Disorders of Reward, Drug Abuse, and Their Treatment I 947

6 The Reactive Reward System -emotional response -impulsivity -automatic/obi igato ry GABA relevance detection FIGURE 19-3 The reactive reward system. The reactive reward system is a "bottom up" system that signals the immediate prospect of either pleasure or pain and provides motivation and behavioral drive to achieve that pleasure or to avoid that pain. For example, internal cues such as craving and withdrawal cause the reactive reward system to trigger drug-seeking behavior. The reactive reward system consists of the ventral tegmental (VTA), which is the site of dopamine cell bodies; the nucleus accumbens, where dopaminergic neurons project; and the amygdala, which has connections with both the VTA and the nucleus accumbens. Rewarding input to the nucleus accumbens is due to bursts of dopamine release and thus phasic dopamine firing with "fun" and potentiation of conditioned reward as the result. Connections of dopaminergic neurons with the amygdala are involved in reward learning (such as memory of pleasure associated with drug abuse), while connections of the amygdala back to the VTA communicate whether anything relevant to a previously experienced pleasure has been detected. Connections of the amygdala with the nucleus accumbens communicate that emotions have been triggered by internal or external cues and signal an impulsive, almost reflexive response to be taken. area accumbens. Spiny neurons in the nucleus accumbens also receive input from the mesolimbic DA pathway (Figure 19-3). Upon repeated exposure to drugs of abuse, this reactive reward system pathologically "learns" to trigger drug seeking behavior and "remembers" how to do this when confronted with internal cues such as craving and withdrawal and external cues from the environment such as people, places, and paraphernalia associated with past drug use. The processes by which plastic changes modify brain circuits are introduced in Chapter 2 and illustrated in Figures 2-22 through Substance abuse is a good example of how the normal mechanisms of learning are hijacked and built into a brain disorder. This is introduced as the concept of "diabolical learning" in Chapter 8 and illustrated in Figure 8-6. Diabolicallearning may apply to different brain circuits not only in addiction but also in chronic pain (discussed in Chapter 15) and for symptoms triggered by stress (discussed in Chapter 14). Connections of the mesolimbic dopamine system within the nucleus accumbens create bursts of dopamine release from phasic dopamine firing, pleasure, reward, and "fun," 948 I Essential Psychopharmacology

7 potentiating the effects of conditioned reward from previous drug abuse experiences (Figure 19-3). Connections of DA neurons with the amygdala are involved with reward learning (Figure 19-3). The amygdala is an important site of emotional learning. For example, the amygdala is involved both in learning about fear (i.e., fear conditioning) and in learning to no longer fear (i.e., fear extinction). This is discussed in Chapter 14 and illustrated in Figures through The amygdala is also involved in learning about reward. As shown in Figure 19-3, connections received from dopamine neurons projecting from the VTA cause the amygdala to develop adaptive changes that condition it to remember the rewards of drug abuse, including not just memory of pleasure but also memory of the environmental cues associated with the pleasurable experience. Once reward learning has been conditioned in the amygdala, connections of the amygdala back to the VTA DA neuron later communicate whether anything relevant to the previously rewarding drug abuse experience is being detected (Figure 19-3). Connections of the amygdala with the nucleus accumbens tell the spiny neurons there that emotional memories have been triggered by internal or external cues, and instruct these spiny neurons to take action impulsively, right away, automatically, obligatorily, and without thought, almost as a reflex action, to find and take more drugs (Figure 19-3). The net result of these changes is that the reactive reward system hijacks the entire reward circuitry when addiction has developed. Individuals in this state are no longer able to base their decisions upon the long-term consequences of their behavior. The reflective reward system: reward from the top down A complementary and in some ways competitive component of the reactive reward system is the reflective reward system, or the "top down" component of reward circuitry (Figure 19-4). This includes important connections from prefrontal cortex down to the nucleus accumbens. These connections are the first legs of cortico-striatal-thalamic-cortical (CSTC) loops, introduced in Chapter 7 and illustrated in Figures 7-18 through CSTC loops are discussed in relation to many different psychiatric disorders throughout this text. Particularly relevant to a discussion of impulsive drug abuse is the discussion of impulsivity in ADHD and the related CSTC loops regulating symptoms in ADHD (discussed in Chapter 17 and illustrated in Figures 17-3 through 17-6). Prefrontal projections from the orbitofrontal cortex may be involved in regulating impulses (Figure 19-4; see also Figures 7-20 and 17-6), whereas prefrontal projections from the dorsolateral prefrontal cortex (DLPFC) may be involved in analyzing the situation, keeping some flexibility of choice in play, and regulating whether it is rational to take an action (Figure 19-4; see also Figures 7-17 and 17-4). Finally, the ventromedial prefrontal cortex (VMPFC; see Figure 7-19) may try to integrate impulsiveness from OFC with analysis and cognitive flexibility from DLPFC with its own regulation of emotions, and come up with a final decision of what to do (Figure 19-4). Additional input for such a final decision also comes from two areas not shown in Figure 19-4: the insula and sensory cortex, contributing feelings about prior experiences of reward and punishment, and the hippocampus, providing contextual information about the decision to be made. When all the inputs are integrated, the final output is either to stop the action that the reactive reward system is triggering (generally drug seeking), or to let it happen. The reflective reward system is built and maintained over time based upon various influences including neurodevelopment, genetics, experience, peer pressure, learning social rules, and learning the benefits of suppressing current pleasure for more valuable future gain (Figure 19-4). The reflective reward system has the power to shape the final output of the Disorders of Reward, Drug Abuse, and Their Treatment I 949

8 The Reflective Reward System emotions impulses GABA final decisioninteg rating emotions/ affect/analysis/im pulses/cogn itive flexi bi Iity FIGURE 19-4 The reflective reward system. Stimulatory input from the "bottom up" reactive reward system is regulated by the "top down" reflective reward system, which consists of projections from the prefrontal cortex to the nucleus accumbens (the "corti co-striatal" portion of corti co-striata I-thalamic-cortical loops). Projections from the orbitofrontal cortex (OFC) are involved in regulating impulses, from the ventromedial prefrontal cortex (VMPFC) are involved in regulating emotions, and from the dorsolateral prefrontal cortex (DLPFC) are involved in analyzing situations and regulating whether an action takes place. reward system into long-term beneficial goal-directed behaviors, such as the will power to resist drugs. When fully developed and functioning properly, the reflective reward system can also provide the motivation for pursuing more naturally rewarding experiences such as education, accomplishments, recognition, financial benefits, career development, enriching social and family connections, etc. Turning reward into goal-directed behavior: output of the reward system The output of the reward system (Figure 19-5) is really just the completion of CSTC loops starting in the prefrontal cortex (see the cortico-striatalleg of the CSTC loop in Figure 19-4 being completed as striatal thalamic and thalamo-cortical projections in Figure 19-5). Specifically, the striatallaccumbens component of reward circuitry has output via GABA-ergic neurons (number 1 in Figure 19-5) that travel to another part of the striatal complex, the ventral pallidum. From there, connections go to the thalamus (number 2 in Figure 19-5), and then back up to the prefrontal cortex, where behaviors are implemented, such as learning and activities resulting in long-term rewards (number 3 in Figure 19-5) or drug-seeking behavior resulting in short-term rewards (number 4 in Figure 19-5). Determining whether the output of the reward system will be converted into short- or long-term rewards is the result of the balance between bottom up reactive reward drives and top down reflective reward decisions (Figures 19-6 through 19-8). For example, the first time you take a drug, there is immediate pharmacological action upon the mesolimbic pleasure 950 Essential Psychopharmacology

9 Turning Reward into Goal-Directed Behavior -learning ~" - long-term rewards ~oort" o ~glu seeking /. - drug short-ter m rewards nucleus accumbens ventral pallidum «m «" thalamus FIGURE 19-5 Turning reward into goal-directed behavior. The second half of the corti co-striata I-thalamiccortical loop is responsible for output of the reward system (i.e., turning reward into goal-directed behavior), GABA-ergic neurons project from the nucleus accumbens to another part of the striatum, the ventral pallidum (1), from which GABA-ergic neurons project to the thalamus (2), Connections from the thalamus project back up to the prefrontal cortex, where behaviors are implemented, such as learning and activities involved in long-term reward (3) or drug-seeking behavior leading to short-term reward (4). center, the exact site of action dependent upon the exact substance ingested (see number 1 in Figure 19-6; see also Figure 19-2). Dopamine is released, pleasure is experienced (number 2 and "wow!" in Figure 19-6), and the amygdala "learns" that this is a rewarding experience (number 3 in Figure 19-6). Reward has now been conditioned in the amygdala. After repetitive rewarding experiences with the drug, the reward circuits become "addicted," so the next time there is an opportunity to use the drug, it is not just the ingesting of the drug that causes dopamine release and pleasure; the cues that predict hedonic pleasure already cause dopamine release (arrow 1 in Figure 19-7). The reward system has learned to anticipate the reward, and that anticipation itself becomes pleasurable. The amygdala signals the dopamine neuron in the VTA that something good is about to happen because it remembers the past drug reward; it may also signal that relief from craving is in sight. Getting the anticipated reward is a very compelling option, so there is a powerful impulse sent to the VTA (arrow 2 in Figure 19-7) triggering DA in the nucleus accumbens (arrow 3 in Figure 19-7) to transform this impulse into the action of finding some drugs and making this reward really happen (arrow 4 in Figure 19-7). Substantial reward and relief is already experienced just by anticipating the reward, but the real kick comes when the drugs are actually ingested again. In addiction, reward is overvalued and hyperactive by virtue of the "diabolical learning" that has occurred in reward circuits. This process of Disorders of Reward, Drug Abuse, and Their Treatment I 951

10 Conditioning to Reward Cues prefrontal cortex reward learning amygdala GABA normal j' baseline Ioveractivation hypoactivation VTA drug FIGURE 19-6 Conditioning to reward cues. The first time a drug is taken (1) it causes immediate release of dopamine (depicted by red color of neurons) and a corresponding experience of pleasure (2). As a result of this the amygdala "learns" that this is a rewarding experience (3). synaptic plasticity changes the efficiency of information flow in the reactive reward circuitry to allow its neuronal activity to preempt all contradictory input coming from the reflective reward circuit in the prefrontal cortex (see hypoactive prefrontal cortex circuits in Figure 19-7). But can impulses from the reactive reward system ever be resisted? What is the role of will power over temptation? That is explained in Figure If temptation is bottom-up demands from the reactive reward system, will power can be seen as top down decision making by the reflective reward system. Specifically, drug seeking is not always an involuntary response to internal and external cues urging that behavior, especially before addiction sets in and when the prefrontal decision-making circuits are well developed and frequently utilized. If addiction is diabolic learning, will power may be virtuous learning within the same reward system (Figure 19-8). Thus, when temptation occurs with the opportunity to ingest drugs arising at a party, in a bar, or when seeing or feeling drugs or their paraphernalia, the amygdala anticipates the pleasure that the drugs would bring (number 1 in Figure 19-8A) by signaling an impulsive choice to the VTA (number 2 in Figure 19-8A) to release dopamine (arrow 3 in Figure 19-8A) that urges output from the nucleus accumbens to engage in behavior that leads to ingesting the drugs again. The OFC in prefrontal cortex is signaling craving and voting for more drug ingestion as well (number 4 in Figure 19-8A). However, this is just temptation. For a split second there may be the opportunity for the DLPFC to think about whether it 952 I Essential Psychopharmacology

11 Compulsive Use/Addiction prefrontal cortex amygdala drug-induced :':.> craving G) ~'.'...'.'.'.'.'.'.'.'.'.' nucleus.iaccumbens ~ drug-seeking behavior \::V o sensitivity reward normal baseline Ioveractivation hypoactivation VTA FIGURE 19-7 Compulsive use/addiction. The amygdala can not only learn that a drug causes pleasure but can also associate cues for that drug with pleasure. Thus, when cues are encountered, the amygdala signals dopamine neurons in the ventral tegmental area (VTA) that something good is coming; it may even signal relief from drug craving (1 and 2). This leads to dopamine release in the nucleus accumbens (3), which triggers GABA-ergic input to the thalamus, thalamic input to the prefrontal cortex, and, unless the reflective reward system is activated (i.e., if the prefrontal neurons were red as opposed to blue), leads to action such as drug-seeking behavior (4). wants to take this action and to cast an opposing vote, showing cognitive flexibility (number 5 in Figure 19-8A), keeping the system from taking an immediate obligatory action just because the reactive reward system is demanding it. Will power can be represented in the reward system as the ability of prefrontal circuits to become activated and prevent impulses being expressed as drug-seeking behavior (Figure 19-8B). Having a functioning top down reflective reward system allows the time to evaluate whether losing your driver's license, getting into an auto accident, losing your job or your relationship is worth becoming intoxicated, and if the answer is no, can trigger the choice of becoming a designated driver and not ingesting the drug (e.g., alcohol) (Figure 19-8B). This is an overly simplistic representation of temptation and will power, but it makes the point that the balance between competing circuits can be tipped in one direction or the other. On the one hand, "diabolical learning" and changes in dominance of the reactive reward system from repeated drug ingestion that overvalues short-term rewards can result in compulsive drug-seeking behavior; on the other hand, "virtuous learning" and plastic changes that lead to dominance of the reflective reward system can produce the ability to suppress short-term rewards for long-term gains. Disorders of Reward, Drug Abuse, and Their Treatment I 953

12 G) drug-induced craving Temptation cognitive flexibility amygdala anticipation of drug (0 ~'.' t~, ~... ':..'. nucleus.,. accumbens <i.' '..--:',..1 A VTA normal baseline ~. overactivation hypoactivation Will Power prefrontal cortex VMPFC DLPFC amygdala.. 'to-,t,:". '<--or '. '. '. '.'.'.'.'.'.'.'.. designated driver B VTA FIGURE 19-8A and B Temptation and will power. Temptation may be seen as "bottom up" demand from the reactive reward system, while will power is a result of "top down" decision making by the reflective reward system. (A) When drug anticipation occurs, (1) this signals an impulsive choice (2) to the ventral tegmental area (VTA) to release dopamine in the nucleus accumbens (3), which in turn produces output to engage in behavior that leads to ingesting drugs again. In the prefrontal cortex, the orbitofrontal cortex (OFC) signals drug-induced cravings and thus supports the "vote" for drug ingestion (4). The dorsolateral prefrontal cortex (DLPFC) interprets the various signals and, showing cognitive flexibility, decides whether to take the action of drug ingestion (5). (B) If the reflective reward system (prefrontal circuits) is activated (shown here by the prefrontal neurons turning red), this can prevent impulses (temptation) from being expressed as behavior, 954 I Essential Psychopharmacology

13 Nicotine How common is smoking in clinical psychopharmacology practices? Some estimates are that more than half of all cigarettes are consumed by patients with a concurrent psychiatric disorder and that smoking is the most common comorbidity among seriously mentally ill patients. It is estimated that about 20 percent of the general population (in the United States) smoke, about 30 percent of people who regularly see general physicians smoke, but that 40 to 50 percent of patients in a psychopharmacology practice smoke, including 60 to 85 percent of patients with ADHD, schizophrenia, and bipolar disorder. Histories of current smoking are often not carefully taken or recorded as one of the diagnoses for smokers in mental health practices. Only about 10 percent of smokers report being offered treatment pro actively by psychopharmacologists and other clinicians. Perhaps this therapeutic nihilism results from the facts that smoking is so addicting and that smoking cessation treatments are so rarely successful. It may also be because the treatment of smoking in patients with psychiatric disorders has been relatively neglected in mental health training programs. Also, companies making smoking cessation treatments tend to spend their efforts educating and marketing to that half of smokers without psychiatric disorders, who may be a more glamorous population associated with less stigma than patients with mental disorders. Nicotine and reward Cigarette smoking is self-administering nicotine in a clever but evil delivery system. Smoking tobacco may be the best way to maximize pleasure from nicotine. Unfortunately, dosing nicotine this way may also maximize the chances of addiction due to the effects that highdose pulsatile delivery of nicotine has on reward circuitry. Tobacco smoking also delivers carcinogens and other toxins that damage the heart, lungs, and other tissues. In terms of psychopharmacological mechanism of action, nicotine acts directly upon nicotinic cholinergic receptors in reward circuits (Figure 19-9 through 19-11). Cholinergic neurons and the neurotransmitter acetylcholine are discussed in Chapter 18 and illustrated in Figures through Nicotinic receptors are illustrated in Figures through There are two major subtypes of nicotinic receptors that are known to be present in the brain, the alpha 4 beta 2 subtype and the alpha 7 subtype (discussed in Chapter 18 and illustrated in Figure 18-15). Nicotine's actions in the ventral tegmental area are those that are theoretically linked to addiction (Figure 19-9). Details of these actions are shown in Figure 19-10, namely, activation of alpha 4 beta 2 nicotinic postsynaptic receptors on DA neurons, leading to DA release in the nucleus accumbens; activation of alpha 7 nicotinic presynaptic neurons on glutamate neurons, which causes glutamate release, and, in turn, DA release in the nucleus accumbens. The release-promoting actions of presynaptic alpha 7 nicotinic receptors on glutamate neurons are discussed in Chapter 18 and illustrated in Figure Nicotine also appears to desensitize alpha 4 beta 2 postsynaptic receptors on inhibitory GABA-ergic interneurons in the VTA (Figure 19-10); this also leads to DA release in nucleus accumbens by disinhibiting dopaminergic mesolimbic neurons. Nicotine and addiction Nicotine has other actions at many nicotinic receptor subtypes and in many areas of the brain. For example, actions of nicotine on postsynaptic alpha 7 nicotinic receptors in the prefrontal cortex may be linked to the pro-cognitive and mentally alerting actions of nicotine but not to addictive actions. However, it is the alpha 4 beta 2 nicotinic receptors on VTA DA neurons that are thought to be the primary targets of nicotine's reinforcing properties Disorders of Reward, Drug Abuse, and Their Treatment 955

14 Actions of Nicotine on Reward Circuits nucleus accumbens VTA FIGURE 19-9 Actions of nicotine on reward circuits. Shown here is the site of action of nicotine on the reactive reward system. Nicotine acts directly upon nicotinic cholinergic receptors in the VTA. (Figure 19-10). These receptors adapt to the chronic intermittent pulsatile delivery of nicotine in a way that leads to addiction (Figure 9-11). That is, initially, alpha 4 beta 2 receptors in the resting state are opened by delivery of nicotine, which in turn leads to dopamine release and reinforcement, pleasure and reward (Figure 19-11A). By the time the cigarette is finished, these receptors become desensitized, so that they cannot function temporarily by reacting to either acetylcholine or nicotine (Figure 19-11A). In terms of obtaining any further reward, you might as well stop smoking at this point. An interesting question to ask is: How long does it take for the nicotinic receptors to desensitize? The answer seems to be: About as long as it takes to inhale all the puffs of a standard cigarette and burn it down to a butt. Thus, it is probably not an accident that cigarettes are the length that they are. Shorter does not maximize the pleasure. Longer is a waste, since by then the receptors are all desensitized anyway (Figure 19-11A). The problem for the smoker is that when the receptors resensitize to their resting state, this initiates craving and withdrawal due to the lack of release of further dopamine 956 I Essential Psychopharmacology

15 VTA nicotine desensitizes V cx4b2 9glu ~ GABA ~ACh <J DA FIGURE Detail of nicotine actions. Nicotine directly causes dopamine release in the nucleus accumbens by binding to alpha 4 beta 2 nicotinic postsynaptic receptors on dopamine neurons in the ventral tegmental area (VTA). In addition, nicotine binds to alpha 7 nicotinic presynaptic receptors on glutamate neurons in the VTA, which in turn leads to dopamine release in the nucleus accumbens. Nicotine also seems to desensitize alpha 4 beta 2 postsynaptic receptors on GABA interneurons in the VTA; the reduction of GABA neurotransmission disinhibits mesolimbic dopamine neurons and thus is a third mechanism for enhancing dopamine release in the nucleus accumbens. (Figure 19-11A). Another interesting question is: How long does it take to resensitize nicotinic receptors? The answer seems to be: About the length of time that smokers take between cigarettes. For the average one-pack-per-day smoker awake for 16 hours, that would be about 45 minutes, possibly explaining why there are 20 cigarettes in a pack (i.e., enough for an average smoker to keep his or her nicotinic receptors completely desensitized all day long). Disorders of Reward, Drug Abuse, and Their Treatment I 957

16 Reinforcement and o<4b2 Nicotinic Receptors resting ~ - DA releases finished \V7 ~q desensitized open ~ cigarette cigarette \[} A initiation of craving Adaptation of 0< 4B2 Nicotinic Receptors W upregulated \[}/w resting \lj7 upregulated, \lj7 \lj7 -+ B ~q desensitized chronically ~ ~ \V7 W ~ ~ancedcraving -+W -+~q Addiction and o<4b2 --- finished cigarettedesensitized open, W reward sensitivity ImpulsIve choices drug-seeking behavior c FIGURE 19-11A, B, and C Reinforcement and alpha 4 beta 2 nicotinic receptors. (A) In the resting state alpha 4 beta 2 nicotinic receptors are closed (left). Nicotine administration, as by smoking a cigarette, causes the receptor to open, which in turn leads to dopamine release (middle). Long-term stimulation of these receptors leads to their desensitization, such that they temporarily can no longer react to nicotine (or to acetylcholine); this occurs in approximately the same length of time it takes to finish a single cigarette (right). As the receptors resensitize, they initiate craving and withdrawal due to the lack of release of further dopamine. (B) With chronic desensitization, alpha 4 beta 2 receptors upregulate to compensate. (C) If one continues smoking, however, the repeated administration of nicotine continues to lead to desensitization of all of these alpha 4 beta 2 receptors and thus the upregulation does no good. In fact, the upregulation can lead to amplified craving as the extra receptors resensitize to their resting state. 958 Essential Psychopharmacology

17 Putting nicotinic receptors out of business by desensitizing them all the time causes neurons to attempt to overcome this lack of functioning receptors by upregulating the number of receptors (Figure 19-11B). That, however, is futile, since nicotine just desensitizes all of them the next time a cigarette is smoked (Figure 19-11C). Furthermore, this upregulation is actually self-defeating, since it serves to amplify the craving that occurs when the extra receptors are resensitizing to their resting state (Figure 19-11C). From a receptor point of view, the goal of smoking is to desensitize all nicotinic alpha 4 beta 2 receptors, get the maximum DA release, and prevent craving. Positron emission tomography (PET) scans of alpha 4 beta 2 nicotinic receptors in human smokers confirm that nicotinic receptors are exposed to just about enough nicotine for just about long enough from each cigarette to accomplish this. Craving seems to be initiated at the first sign of nicotinic receptor resensitization. Thus, the bad thing about receptor resensitization is craving. The good thing from a smoker's point of view is that as the receptors resensitize, they are available to release more dopamine and cause pleasure again. Treatment of nicotine addiction Treating nicotine dependence is not easy. There is evidence that nicotine addiction begins with the first cigarette, with the first dose showing signs oflasting a month in experimental animals (e.g., activation of the anterior cingulate cortex for this long after a single dose). Craving begins within a month of repeated administration. Perhaps even more troublesome is the finding that the "diabolical learning" that occurs from substance abuse of all sorts, including nicotine, may be very, very long-lasting once exposure is stopped. Some evidence suggests that these changes even last a lifetime with a form of "molecular memory" to nicotine, even in long-term-abstinent former smokers. It is quite clear that the 4- to 12 week periods of treatment often employed in testing treatments for addiction are nowhere close to long enough to reverse the molecular changes in the reward circuitry of a nicotine addict. Currently experts hypothesize that reward conditioning may be very similar to fear conditioning, with both occurring in the amygdala (see Figure 14-40). Just as fear conditioning may be permanently engrained in the amygdala when it occurs, so may reward conditioning. The process of getting over fear is not passive, waiting for the amygdala to "forget," but rather an active one of new learning that inhibits the old. Unfortunately the new learning does not seem to be as strong as the old, and without "practice" and reinforcement of the new learning, it is possible for that new learning to fade away in a process called "renewal forgetting" and thus renewal of fear (see Figure 14-40). By analogy, reward learning may require active learning and active reinforcement of that new learning in order to counter the craving and drug-seeking behavior, even months after the last ingestion of substance. Furthermore, the reward circuitry may always be at risk of "snapping back" into an addicted state due to engrained molecular memories, with only one "slip" and one reuse of the previously abused substance. It may be that one never forgets how to smoke or take any other substance once one is addicted to it. Thus it may not be unreasonable to predict, for substance abuse in general and for nicotine addiction in particular, that treatment periods of more than a year may be required to attain a state of sustained abstinence with reduced risk of relapse. Few available treatments for substance abuse are administered this way, and few studies are available to guide long-term use of these agents. Thus one of the greatest unmet needs regarding currently available smoking cessation treatments is research about how long to continue treatment after smoking has stopped. Another important gap in smoking cessation therapeutics is that it is not known how Disorders of Reward, Drug Abuse, and Their Treatment I 959

18 FIGURE Alpha 4 beta 2 agonists and partial agonists. Shown here are icons for acetylcholine, nicotine, and nicotinic partial agonists (NPAs), all of which bind nicotinic cholinergic receptors. ACh nicotine NPA effective repeat quit attempts are over time. Many patients try to quit smoking and fail. Do additional attempts to quit increase the chances oflong-term success in quitting, or are they just futile? What about in psychiatric disorders such as ADHD, schizophrenia, and depression where patients may not only be addicted but also using nicotine to self-medicate their psychiatric disorder? Although many smokers try to quit and fail, the same can be said for learning how to ride a bike or a horse. There is an old saying among horse riders that it takes seven falls to make a rider, so get back up on the horse when you fall. It may also take seven (or more) quit attempts to make a substance abuser a successful quitter, but there is little research on this. For treating nicotine dependence with psychopharmacological agents, one of the first successful agents proven to be effective is nicotine itself (Figure 19-12), but in a route of administration other than smoking: gums, lozenges, nasal sprays, inhalers, and most notably transdermal patches. Delivering nicotine by these other routes does not produce the high levels or the pulsatile blasts that are delivered to the brain by smoking, so they are not very reinforcing. However, alternative delivery of nicotine can help to reduce craving due to a steady amount of nicotine that is delivered and presumably desensitizes an important number of resensitizing and craving nicotinic receptors. The leading treatment for nicotine dependence may be the newly introduced nicotinic partial agonist (NPA) varenicline, a selective alpha 4 beta 2 nicotinic acetylcholine receptor partial agonist (Figure 19-12). Figure contrasts the effects of NPAs with nicotinic full agonists and with nicotinic antagonists on the cation channel associated with nicotinic cholinergic receptors. Nicotinic full agonists include acetylcholine, a short-acting full agonist, and nicotine, a long-acting full agonist. They open the channel fully and frequently (Figure 19-13, on the left). By contrast, nicotinic antagonists stabilize the channel in the closed state but do not desensitize these receptors (Figure 19-13, on the right). NPAs stabilize nicotinic receptors in an intermediate state, which is not desensitized and where the channel is open less frequently than with a full agonist but more frequently than with an antagonist (Figure 19-13, middle). Varenicline is the first NPA to be approved for smoking cessation in the United States, but it is now known that a plant alkaloid called cytisine and used in eastern Europe for over 40 years for smoking cessation is also an NPA. Its poor brain penetration may limit its efficacy. Another selective alpha 4 beta 2 NPA in clinical testing is dianicline (SSR ). Within the reward circuitry, the important sites of action of the NPA varenicline are at alpha 4 beta 2 sites in the VTA, particularly those receptors located directly on mesolimbic DA neurons (Figure 19-14). These actions are contrasted with those of acetylcholine and nicotine at this same site in Figures through The full agonist acetylcholine (Figure 19-15) is short-acting because of the ubiquity of the enzyme acetylcholinesterase, 960 Essential Psychopharmacology

19 Molecular Actions of a Nicotinic Partial Agonist (NPA) nicotinic full agonist: channel frequently open nicotinic partial agonist (NPA): stabilizes channel in less frequently open state, not desensitized nicotinic antagonist: stabilizes channel in closed state, not desensitized FIGURE Molecular actions of a nicotinic partial agonist (NPA). Full agonists at alpha 4 beta 2 receptors, such as acetylcholine and nicotine, cause the channels to open frequently (left). In contrast, antagonists at these receptors stabilize them in a closed state, such that they do not become desensitized (right). Nicotinic partial agonists (NPAs) stabilize the channels in an intermediate state, causing them to open less frequently than a full agonist but more frequently than an antagonist (middle). always on the ready to destroy acetylcholine. The actions of acetylcholinesterase are introduced in Chapter 18 and illustrated in Figures and through Because of the short-acting nature of acetylcholine at alpha 4 beta 2 nicotinic receptors on VTA DA neurons, it causes a short burst of action potentials and a similar short pulse ofda release in the nucleus accumbens (Figure 19-15). This is the physiological action of neurotransmitters regulating DA release in the reward pathway. It is the type ofda release associated with a stimulus that is novel, interesting, relevant, or fascinating to the individual. These features of a nondrug stimulus that can provoke the release of neurotransmitters such as acetylcholine and thus a short burst ofda in the nucleus accumbens are sometimes said to be "salient." When nicotine occupies these same alpha 4 beta 2 nicotinic receptors on DA neurons in the VTA, it causes an abnormally prolonged burst of action potentials until the nicotinic receptor desensitizes (Figure 19-16). Nicotine is long-acting because it is not destroyed by acetylcholinesterase. The prolonged burst of action potentials is accompanied by an abnormally prolonged and supraphysiological release ofda in the nucleus accumbens, creating pleasure until the nicotinic receptors desensitize, and creating craving as the nicotinic receptors begin to resensitize. Finally, when an NPA like varenicline occupies these receptors, the result is a lowergrade increase in the frequency of action potentials, with consequent sustained but small amounts of DA release (Figure 19-17). Rather than the "glare of spotlights" from the excessive DA release that occurs with nicotine, NPAs have been described as leaving a "night light" ofda on, without desensitizing nicotinic receptors, sufficient to reduce craving but not sufficient to cause euphoria. Another way to compare the actions of nicotine and NPAs is shown in Figures and When a person is smoking, nicotine arterial levels and brain levels rise with each puff and fall between puffs (Figure 19-18A). Immediately following the smoking of a single cigarette, nicotine levels are sufficiently high to keep the receptors desensitized for Disorders of Reward, Drug Abuse, and Their Treatment I 961

20 Varenicline Actions on Reward Circuits "{}7 cx4b2 9- glu ~ GABA ~ACh <7 DA FIGURE Varenicline actions on reward circuits. Varenicline is a nicotinic partial agonist (NPA) selective for the alpha 4 beta 2 receptor subtype. Its actions at alpha 4 beta 2 nicotinic receptors - located on dopamine neurons, glutamate neurons, and GABA interneurons in the VTA - are all shown. a while; but when nicotine levels fall over time, nicotinic receptors begin to resensitize and cause craving. In order to treat the craving without causing euphoria, one approach is to use nicotine in a transdermal delivery system that produces steady levels of nicotine, taking the edge off of craving due to occupying and desensitizing at least some nicotinic receptors (Figure 19-18B). The problem with this approach and related approaches of nicotine gum and inhaled nicotine, etc., is that the level of nicotine achieved at VTA receptors is often not sufficient to reduce craving to a satisfactory level. This leads to impulsive smobng to relieve 962 I Essential Psychopharmacology

21 Acetylcholine and DA Release short pulse of DA release short burst of action potentials cj = ACh o = Ca2+ ~ =DA FIGURE Acetylcholine and dopamine release. Acetylcholine is a full agonist at alpha 4 beta 2 nicotinic receptors located on dopamine neurons in the ventral tegmental area (VTA); however, it is also short-acting due to its quick breakdown by acetylcholinesterase (AChE). Thus acetylcholine triggers a short burst of action potentials and a resultant short pulse of dopamine release in the nucleus accumbens. craving. Nicotine replacement therapies can all be "smoked over," meaning that despite receiving nicotine by an alternate route of administration, it is possible to simultaneously smoke in order to achieve pleasure and completely abolish craving (Figure 19-19B). This rather defeats the purpose of the alternate route of nicotine administration. Contrast this to the actions ofnpas (Figure 19-19). Shown here is the response level of a smoker in withdrawal (Figure 19-19A on the far left) who then has all of his nicotinic receptors partially activated with an NPA (Figure 19-19A on the left), with generally more reduction in craving than can be achieved with subreinforcing levels of transdermal nicotine, shown in Figure 19-18B. Furthermore, when that same smoker is given an NPA while smoking, nicotine delivery via smoking is no longer rewarding, since the alpha 4 beta 2 receptors become occupied by an agent that allows only partial receptor activation. Thus, NPAs cannot be "smoked over" (Figure 19-19B). This can be an important therapeutic Disorders of Reward, Drug Abuse, and Their Treatment I 963