* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Stahl_3rd_ch19_Part2..
Survey
Document related concepts
Aging brain wikipedia , lookup
Neuromuscular junction wikipedia , lookup
Biology and sexual orientation wikipedia , lookup
Biology of depression wikipedia , lookup
Neuroeconomics wikipedia , lookup
Stimulus (physiology) wikipedia , lookup
Hypothalamus wikipedia , lookup
Synaptic gating wikipedia , lookup
Endocannabinoid system wikipedia , lookup
Sexual dysfunction wikipedia , lookup
Molecular neuroscience wikipedia , lookup
Neurotransmitter wikipedia , lookup
Transcript
Actions of Acamprosate in the VTA: Reducing Excessive Glutamate Release to Relieve Withdrawal VTA 9- glu 6 /J!J. JA opiate receptor VSCC 'W" GABA o <J ~ mGluR receptor m NMDA receptor en kephalin Jt GABA-B receptor DA t1 GABA-A receptor FIGURE 19-29 Actions of acamprosate in the ventral tegmental area (VTA). Acamprosate seems to block glutamate receptors, particularly metabotrophic glutamate receptors (mGluRs) and perhaps also N-methyl-daspartate (NMDA) receptors. When alcohol is taken chronically and then withdrawn, the adaptive changes that it causes in both the glutamate system and the GABA system create a state of glutamate overexcitation as well as GABA deficiency. By blocking glutamate receptors, acamprosate may thus mitigate glutamate hyperexcitability during alcohol withdrawal. 978 I Essential Psychopharmacology Actions of Opiates on Reward Circuits nucleus accumbens VTA FIGURE 19-30 Actions of opiates on reward circuits. Neurons originating in the arcuate nucleus project to both the ventral tegmental area (VTA),site of dopamine cell bodies and also where many neurotransmitters project, and the nucleus accumbens, to which dopaminergic neurons project. Opiate neurons release endogenous opiates such as enkephalin. which may last several hours, followed in turn by drowsiness ("nodding"), mood swings, mental clouding, apathy, and slowed motor movements. In overdose, these same agents act as depressants reversed of respiration by synthetic and can also induce coma. The acute actions of opiates can be opiate antagonists such as naloxone and naltrexone, as antagonists at opiate receptors. When given chronically, opiates easily cause both tolerance which and dependence. compete Adapta- tion of opiate receptors occurs quite readily after chronic opiate administration. The first sign of this is the patient's need to take higher and higher doses of opiate in order to relieve pain or induce the desired euphoria. Eventually, that causes euphoria and that which produces sign that dependence their sensitivity has occurred to agonist actions there may be little room between the toxic effects of an overdose. and that opiate receptors is the production have adapted of a withdrawal the dose Another by decreasing syndrome Disorders of Reward, Drug Abuse, and Their Treatment once the I 979 Endogenous Opiate Neurotransmitters FIGURE 19-31 Endogenous opiate neurotransmitters. Opiate drugs act on a variety of receptors called opiate receptors, the most important of which are mu, delta, and kappa. Endogenous opiate-like substances are peptides derived from precursor proteins called POMC (pro-opiomelanocortinJ, proenkephalin, and prodynorphin. Parts of these precursor proteins are cleaved off to form endorphins, enkephalins, or dynorphin, which are then stored in opiate neurons and presumably released during neurotransmission to mediate reinforcement and pleasure. chronically administered opiate wears off. Opiate antagonists such as naloxone can precipitate a withdrawal syndrome in opiate-dependent persons. This syndrome is characterized by feelings of dysphoria, craving for another dose of opiate, irritability, and signs of autonomic hyperactivity such as tachycardia, tremor, and sweating. Piloerection ("goose bumps") is often associated with opiate withdrawal, especially when a drug is stopped suddenly ("cold turkey"). This is so subjectively horrible that the opiate abuser will often stop at nothing in order to get another dose of opiate to relieve such symptoms. Thus, what may have begun as a quest for euphoria may end up as a quest to avoid withdrawal. Clonidine, an alpha 2 adrenergic agonist, can reduce signs of autonomic hyperactivity during withdrawal and aid in the detoxification process. In the early days of opiate use/abuse/intoxication and prior to the completion of the neuroadaptive mechanisms that mediate opiate receptor desensitization, opiate intoxication in the abuser alternates with normal functioning. Later, after the opiate receptors adapt and the person becomes dependent, he or she may experience very little euphoria but mostly a state of lack of withdrawal alternating with the presence of withdrawal. Treatment of opiate dependence Opiate receptors can readapt to normal if given a chance to do so in the absence of additional intake of drug. This may be too difficult to tolerate, so reinstituting another opiate, 980 Essential Psychopharmacology Methadone opiate full agonist FIGURE 19-32 Buprenorphine opiate partial agonist (OPA) Icons of methadone and buprenorphine. Methadone, a full agonist at opiate receptors, and buprenorphine, a partial agonist at opiate receptors, are both used during detoxification from exogenous opiates such as codeine, morphine, and heroin. such as methadone, which can be taken orally and then slowly tapered, may assist in the detoxification process (Figure 19-32). A partial mu opiate agonist, buprenorphine, now available in a sublingual dosage formulation combined with naloxone, can also substitute for stronger full agonist opiates and then be tapered. It is combined with the opiate naloxone, which does not get absorbed orally or sublingually but prevents intravenous abuse, since injection of the combination of buprenorphine plus naloxone results in no high and may even precipitate withdrawal. L-alpha-acetylmethodol acetate (LAAM) is a long-acting orally active opiate with pharmacological properties similar to those of methadone, but it is rarely used because of concerns over QTc prolongation. Agonist substitution treatments are best used in the setting of a structured maintenance treatment program that includes random urine drug screening and intensive psychological, medical, and vocational services. For heavy-duty opiate addicts, specialty methadone clinics may be useful. As for other areas of drug abuse, rank-and-file office-based psychopharmacologists use very little of the agonist substitution process for treating opiate abusers or addicts, including relatively little use of buprenorphine. This situation is likely the product of therapeutic nihilism for opiate addicts and probably also the wish not to have heroin and serious intravenous opiate addicts in one's practice, since they often must live on the streets, tend to engage in criminal activities, and are highly unreliable. However, for motivated prescription opiate addicts who are still employed, reliable, and less likely to be involved with crime or living on the street and who have not taken methadone previously, buprenorphine may remain a viable option. Stimulants Use of stimulants as therapeutic agents is discussed extensively in several other chapters. Mechanism of action of amphetamine as an inhibitor of the dopamine transporter (DAT) and also of the vesicular monoamine transporter (VMAT) is introduced in Chapter 4 and illustrated in Figure 4-15. Therapeutic use of stimulants for sleep/wake disorders is discussed in Chapter 16 and illustrated in Figures 16-3, 16-5, 16-31, and 16-32. Therapeutic use of stimulants for ADHD is discussed in Chapter 17 and illustrated in Figures 17-8, 17-9, 17-18,17-19, and 17-20. Disorders of Reward, Drug Abuse, and Their Treatment I 981 Actions of Stimulants on Reward Circuits nucleus accumbens stimulants VTA FIGURE 19-33 Actions of stimulants on reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA), site of dopamine cell bodies which also receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTA and the nucleus accumbens. The potential abuse properties of stimulants stem from their ability to enhance dopamine release in the nucleus accumbens. Stimulants and reward The mechanisms of enhanced reinforcement and abusability of stimulants when given in high pulsatile doses are compared and contrasted with the reduced reinforcement of stimulants when given in oral sustained release dosing in Figures 17-18 through 17-20. Although many therapeutic actions of stimulants are thought to be directed to the prefrontal cortex and also to the enhancement of both norepinephrine and dopamine neurotransmission there, the actions of stimulants that are linked to their abuse are thought to be primarily those that target reward circuits, especially dopamine release from mesolimbic dopamine neurons in the nucleus accumbens (Figure 19-33). One stimulant without recognized therapeutic uses in psychopharmacology is cocaine (Figure 19-34). This agent has two major properties: it is both a local anesthetic and an 982 I Essential PSYChopharmacology FIGURE 19-34 Icon of cocaine. The Cocaine main mechanism of action of cocaine is DA to block reuptake and cause the release of monoamines, principally dopamine (DA) but also norepinephrine (NE) and serotonin (5HT). There is also a local anesthetic action (caine). NE 5HT caine inhibitor of monoamine transporters, especially for dopamine (i.e., DAT, the DA transporter). But often neglected in discussions of cocaine is consideration of its ability to inhibit the serotonin transporter (SERT) and the norepinephrine transporter (NET) (Figure 19-34). Cocaine's local anesthetic properties are still used in medicine, especially by earnose-and-throat specialists (otolaryngologists). Freud himself exploited this property of cocaine to help dull the pain of his tongue cancer. He may have also exploited the second property of the drug, which is to produce euphoria, reduce fatigue, and create a sense of mental acuity due to inhibition of dopamine reuptake at the dopamine transporter. Cocaine inhibits DAT in a manner similar to the action of methylphenidate. That is, cocaine is a blocker of transport of DA by DAT. Cocaine does not act upon dopamine neurons as amphetamine does, but methamphetamine (Figure 19-35) acts just like amphetamine, only faster. In addition, methamphetamine is converted to amphetamine. Amphetamine and methamphetamine are both pseudosubstrates and reverse transporters of DA via DAT and also inhibitors ofVMAT. These properties of amphetamine are discussed in Chapter 4 and illustrated in Figure 4-15. So what is the difference between methylphenidate and cocaine if they both have the same mechanism of action? Similarly, what is the difference between amphetamine for ADHD and methamphetamine for abuse? The answers are not in differences in mechanism of action but in route of administration and therefore how fast, how powerfully, and how completely DAT is blocked. Methylphenidate is taken orally and is longer in onset and duration of action compared to stimulants that are injected, snorted intranasally, or smoked. Methylphenidate itself is Disorders of Reward, Drug Abuse, and Their Treatment I 983 Amphetamine Methamphetamine FIGURE 19-35 Icon of amphetamine/ methamphetamine. Amphetamine and methamphetamine are both pseudosubstrates and reverse transporters of dopamine via the dopamine transporter (OAT) and also act as inhibitors of the vesicular monoamine transporter (VMAT). far more abusable when injected; but even injected, methylphenidate does not seem to blast the DAT as ferociously as do other stimulants injected intravenously. Cocaine is not active orally, so users have learned over the years to take it intranasally, where the drug rapidly enters the brain directly, bypassing the heart, and thus can have a more rapid onset than even with intravenous administration. The most rapid and robust way to deliver drugs to the brain is to smoke those that are compatible with this route of administration, as this avoids first-pass metabolism through the liver and is somewhat akin to giving the drug by intra-arterial/in tracarotid bolus. As stated in previous chapters, blasting DAT in a dramatic pulsatile manner maximizes the chances for phasic DA release (see Figure 17-20), which is highly reinforcing and pleasurable when this happens in the nucleus accumbens. Taking huge oral doses of a stimulant with rapid onset, or taking it intranasally, intravenously, or smoking it can create highly intense pleasurable experiences that are often described by addicts as better than orgasm. At intoxicating doses of cocaine or methamphetamine, however, undesirable effects can be produced, including tremor, emotional lability, restlessness, irritability, paranoia, panic, and repetitive stereotyped behavior. At even higher doses, these stimulants can induce intense anxiety, paranoia, and hallucinations, with hypertension, tachycardia, ventricular irritability, hyperthermia, and respiratory depression. In overdose, cocaine can cause acute heart failure, stroke, and seizures. Long-term effects of stimulant abuse Even worse for DA neurons than high doses may be effects of repetitive intoxicating doses of stimulants on these neurons. The progression of stimulant abuse is shown in Figure 19-36. First doses of stimulants cause pleasurable phasic dopamine neuronal firing (Figure 19-36A). Eventually, reward conditioning occurs, causing craving between stimulant doses and lack of pleasurable phasic dopamine firing, with only residual tonic dopamine neuronal firing (Figure 19-36B). Now that the user is addicted, higher and higher doses 984 Essential Psychopharmacology Progression of Stimulant Abuse I® enduring I cognitive loss "burn~out" time B, C, D, E, and F Progression of stimulant abuse. (A) First doses of stimulants such as amphetamine or cocaine cause pleasurable phasic dopamine firing. (B) With chronic use, reward conditioning causes craving between stimulant doses and only residual tonic dopamine firing with lack of pleasurable phasic dopamine firing. (C) In this addicted state, higher and higher doses of stimulants are needed in order to achieve the pleasurable highs of phasic dopamine firing. (D) Unfortunately, the higher the high, the lower the low, and between stimulant doses the individual experiences not only the absence of a high but also withdrawal symptoms such as sleepiness and anhedonia. (E) The effort to combat withdrawal can lead to compulsive use and impulsive, dangerous behaviors in order to secure the stimulant. (F) Finally,there may be enduring if not irreversible changes in dopamine neurons, including long-lasting depletions of dopamine levels and axonal degeneration, a state that clinically and pathologically is appropriately called "burn-out." FIGURE 19-36A, must be taken to get better and better "highs" that accompany phasic dopamine neuronal firing (brainwashed; Figure 19-36C). Unfortunately, the higher the high, the lower the low, and between stimulant doses the experience is that of sleepiness and anhedonia, not just the absence of a high (withdrawal; Figure 19-36D). To avoid this state and get ever more satisfYing highs, the situation progresses to compulsive use, often with marathon, indiscriminate, and unprotected sex, risk of HIV from shared needles and sex, with the emergence of paranoia (Figure 19-26E). Indeed, stimulants can produce a paranoid psy- chosis indistinguishable from acute paranoid schizophrenia, as discussed in Chapter 9 and illustrated in Figures 9-25 and 9-26. At this stage, the addict is often involved with criminal activity in order to obtain drugs and with people and situations that trigger violence (Figure 19-36E). Finally, there may be enduring if not irreversible changes in dopamine neurons, including long-lasting depletion of dopamine levels and axonal degeneration, a state that clinically and pathologically is appropriately called "burn-out" (Figure 19-36F). This can be associated with enduring cognitive loss and treatment-resistant depression, and it can take a very long time, sometimes years, to reverse if at all. Although there are no approved treatments for stimulant there may be a cocaine vaccine (TA-CD) in the future abusers or stimulant that removes addicts, the drug before it can lead the patient along the route of progression of stimulant abuse shown in Figure 19-36. The weak DAT inhibitor modafinil is also being tested, as are various antipsychotics Disorders of Reward, Drug Abuse, and Their Treatment I 985 such as olanzapine, but particularly D2 partial agonists such as aripiprazole. Experimental treatments include dopamine D3 receptor partial agonists (RGH188, BP987) or antagonists (NGB2904, SB277011A, ST198) and long-lasting dopamine releasers such as PAL287. Naltrexone is also being investigated. N-acetyl cysteine, a precursor of the amino acid cysteine, acts on the cysteine-glutamate exchange mechanism - which may be disordered in cocaine-dependent individuals seeking drugs - to reduce craving and interest in cocaine. Sedative hypnotics Sedative hypnotics include barbiturates and related agents such as ethchlorvynol and ethinamate, chloral hydrate and derivatives, and piperidinedione derivatives such as glutethimide and methyprylon. Experts often include alcohol, benzodiazepines, and Z drug hypnotics in this class as well. The mechanism of action of sedative hypnotics is basically the same as that of those described in Chapter 14 and illustrated in Figures 14-20 and 14-22 for the action ofbenzodiazepines: namely, they are positive allosteric modulators (PAMs) for GABA-A receptors. Actions of sedative hypnotics at GABA-A receptor sites in reward circuits are shown in Figure 19-37. Molecular actions of all sedative hypnotics are similar, but benzodiazepines and barbiturates seem to work at different sites from each other and also only on some GABA-A receptor subtypes, namely those with alpha 1, alpha 2, alpha 3, or alpha 5 subunits (Figure 19-38A). Barbiturates are much less safe in overdose than benzodiazepines, cause dependence more frequently, are abused more frequently, and produce much more dangerous withdrawal reactions. Apparently the receptor site at GABA -A receptors mediating the pharmacological actions of barbiturates (Figure 19-38A) is even more readily desensitized with even more dangerous consequences than the benzodiazepine receptor (also shown in Figure 19-38). The barbiturate site must also mediate a more intense euphoria and a more desirable sense of tranquility than the benzodiazepine receptor site. Since benzodiazepines are generally an adequate alternative to barbiturates, psychopharmacologists can help to minimize abuse of barbiturates by prescribing them rarely if ever. In the case of withdrawal reactions, reinstituting and then tapering the offending barbiturate under close clinical supervision can assist the detoxification process. Marijuana You can indeed get stoned without inhaling (Figure 19-39)! Actions of marijuana and its active ingredient THC (delta-9-tetrahydrocannabinol) on reward circuits are shown in Figure 19-39 at sites where endogenous cannabinoids are utilized naturally as retrograde neurotransmitters. The concept of the "brain's own marijuana" is introduced in Chapter 3 and retrograde neurotransmission with these endogenous cannabinoids (or "endocannabinoids") at CB1 presynaptic cannabinoid receptors is illustrated in Figure 3-3. Cannabis preparations are smoked in order to deliver cannabinoids that interact with the brain's own cannabinoid receptors to trigger dopamine release from the mesolimbic reward system (Figure 19-39). Marijuana can have both stimulant and sedative properties. In usual intoxicating doses, it produces a sense of well-being, relaxation, a sense of friendliness, a loss of temporal awareness including confusing the past with the present, slowing of thought processes, impairment of short-term memory, and a feeling of achieving special insights. At high doses, marijuana can induce panic, toxic delirium, and rarely psychosis. One complication oflong-term use is the "amotivational syndrome" in frequent users. This syndrome is seen predominantly in heavy daily users and is characterized by the emergence of decreased drive and ambition, thus "amotivation." It is also associated 986 I Essential Psychopharmacology Actions of Sedative Hypnotics and Benzodiazepines on Reward Circuits nucleus accumbens VTA sedative hypnotics! benzodiazepines FIGURE 19-37 Actions of sedative hypnotics and benzodiazepines on reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA) , site of dopamine cell bodies that receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTA and the nucleus accumbens. Sedative hypnotics and benzodiazepines are positive allosteric modulators at GABA-A receptors (such as in the VTA, as shown here). with other socially and occupationally impairing symptoms, including a shortened attention span, poor judgment, easy distractibility, impaired communication skills, introversion, and diminished effectiveness in interpersonal situations. Personal habits may deteriorate, and there may be a loss of insight and even feelings of depersonalization. In terms of chronic administration to humans, tolerance to cannabinoids has been well documented, but the question of cannabinoid dependence has always been controversial. The discovery of the brain cannabinoid CEI receptor antagonist rimonabant has settled this question in experimental animals because it precipitates a withdrawal syndrome in mice chronically exposed to THC. It is therefore highly likely but not yet proven that dependence also occurs in humans, presumably due to the same types of adaptive changes in cannabinoid receptors Disorders of Reward, Drug Abuse, and Their Treatment 987 Binding Sites for Sedative Hypnotic Drugs chloride channel GABA binding site BZ binding site ~ barbiturate binding site A benzodiazepine receptors: D(1, D(2, D(3, D( 5 subtypes chloride channel neurosteroid binding site ? alcohol binding site general anesthetics benzodiazepine receptors: 6subtypes (alpha 4, alpha 6) B FIGURE 19-38A and B Binding sites for sedative hypnotic drugs. (A) Benzodiazepines and barbiturates both act at GABA-A receptors, but at different binding sites. Benzodiazepines do not act at all GABA-A receptors; rather, they are selective for the alpha 1,2,3, and 5 subtypes. (B) General anesthetics, alcohol, and neurosteroids may bind to other types of GABA-A receptors. 988 I Essential Psychopharmacology Actions of Marijuana and THC on Reward Circuits nucleus accumbens VTA THC FIGURE 19-39 Actions of marijuana and THC on reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA), site of dopamine cell bodies that receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTAand the nucleus accumbens. Marijuana delivers its active ingredients, the cannabinoids (e.g., THC; delta-9-tetrahydrocannabinol), which interact with the brain's own cannabinoid receptors to trigger dopamine release in the nucleus accumbens. that occur in other neurotransmitter of abuse. There receptors are two known cannabinoid after chronic receptors, CEI administration of other drugs (in brain) and CE2 (predominantly in the immune system). CEI receptors may mediate not only marijuana's reinforcing properties but also those of alcohol and to some extent those of other psychoactive substances (including food, if sugars and fats can be considered "psychoactive"; this is discussed further on). Anandamide is one of the endocannabinoids and a member of a chemical class of neurotransmitter that is not a monoamine, not an amino acid, and not a peptide: it is a lipid, specifically a member of a family of fatty acid ethanolamides. Anandamide shares most but not all of the pharmacological properties of THC, since its actions at brain cannabinoid Disorders of Reward, Drug Abuse, and Their Treatment I 989 receptors are not only mimicked by TH C but also antagonized in part by the selective brain cannabinoid CBl receptor antagonist rimonabant. The discovery of rimonabant, a "marijuana antagonist," has opened the door to using this drug as a potential therapeutic agent in various types of drug abuse, from cigarette smoking to alcoholism to marijuana abuse. Additionally, rimonabant has been extensively tested in obesity and the metabolic syndrome and has received approved for this use in some countries. However, approval in the United States has not been granted yet due to concerns about the possibility that long-term use of rimonabant might increase suicidal ideation. Hallucinogens The hallucinogens are a group of agents that act at serotonin synapses in the reward system (Figure 19-40). They produce intoxication, sometimes called a "trip," associated with changes in sensory experiences, including visual illusions and hallucinations and an enhanced awareness of both external and internal stimuli and thoughts. These hallucinations are produced with a clear level of consciousness and a lack of confusion and may be both psychedelic and psychotomimetic. "Psychedelic" is the term for a heightened sensory awareness and subjective experience that one's mind is being expanded, that one is in union with all humanity or the universe, and that one is having a sort of religious experience. "Psychotomimetic" means that the experience mimics a state of psychosis, but the resemblance between a trip and psychosis is superficial at best. As previously discussed, the stimulants cocaine and amphetamine much more genuinely mimic psychosis. Hallucinogen intoxication includes visual illusions, visual "trails" where the image smears into streaks of its image as it moves across a visual trail, macropsia and micropsia, emotional and mood lability, subjective slowing of time, the sense that colors are heard and sounds are seen, intensification of sound perception, depersonalization and derealization, yet retaining a state of full wakefulness and alertness. Other changes may include impaired judgment, fear oflosing one's mind, anxiety, nausea, tachycardia, increased blood pressure, and increased body temperature. Not surprisingly, hallucinogen intoxication can cause what is perceived as a panic attack, which is often called a "bad trip." As intoxication escalates, one can experience an acute confusional state (delirium) of disorientation and agitation. This can evolve further into frank psychosis, with delusions and paranoia. Common hallucinogens include two major classes of agents. The first class resemble serotonin (indo1ea1ky1amines) and include the classic hallucinogens LSD (d-1ysergic acid diethylamide), psilocybin, and dimethyltryptamine (DMT) (Figure 19-41). The second class of agents resemble norepinephrine and dopamine and are also related to amphetamine (pheny1a1ky1amines); they include mescaline DOM (2,5-dimethoxy-4methy1amphetamine) and others. More recently, synthetic chemists have come up with some new "designer drugs" such as MDMA (3,4-methy1ene-dioxymethamphetamine) and "Foxy" (5-methoxy-diisopropyltryptamine). These are either stimulants or hallucinogens and produce a complex subjective state sometimes referred to as "ecstasy," which is also what abusers call MDMA itself. MDMA produces euphoria, disorientation, confusion, enhanced sociability, and a sense of increased empathy and personal insight. Hallucinogens have rather complex interactions at neurotransmitter systems, but one of the most prominent is a common action as agonists at 5HT2A receptor sites (Figure 19-42). Hallucinogens certainly have additional effects at other 5HT receptors (especially 5HT1A somatodendritic autoreceptors and 5HT2C receptors) and also at other neurotransmitter systems, especially norepinephrine and dopamine, but the relative importance of these other 990 I Essential Psychopharmacology Actions of Hallucinogens on Reward Circuits nucleus accumbens hallucinogens \ VTA FIGURE 19-40 Actions of hallucinogens on reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA), site of dopamine cell bodies that receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTA and the nucleus accumbens. Hallucinogens act at serotonin synapses within this reward system. actions is less well known. MDMA also appears to be a powerful inhibitor of the serotonin transporter (SERT) (Figure 19-42) and is also a releaser of 5HT. MDMA and several other drugs structurally related to it may even destroy serotonin axon terminals. However, the action that appears to explain a common mechanism for most of the hallucinogens is the stimulation of 5HT2A receptors. Hallucinogens can produce incredible tolerance, sometimes after a single dose. Desensitization of 5HT2A receptors is hypothesized to underlie this rapid clinical and pharmacological tolerance. Another unique dimension of hallucinogen abuse is the production of "flashbacks," namely the spontaneous recurrence of some of the symptoms of intoxication that lasts from a few seconds to several hours, but in the absence of recent administration of the hallucinogen. This occurs days to months after the last drug experience and can Disorders of Reward, Drug Abuse, and Their Treatment I 991 FIGURE 19-41 Serotonergic Hallucinogens MDMA Icons of hallucinogens. Hallucinogens such as lysergic acid diethylamide (LSD), mescaline, psilocybin, and 3,4-methylenediosymethamphetamine (MDMA) are agonists at serotonin 2A (5HT2A) receptors. V 5HT2A psilocybin LSD 5HT2A 5HT2A mescaline o 5HT2A FIGURE 19-42 5HT neuron Actions of hallucinogens. The primary action of hallucinogenic drugs such as LSD, mescaline, psilocybin, and MDMA are shown here: namely, agonism of 5HT2A receptors. Hallucinogens may have additional actions at other serotonin receptors (particularly 5HTlA and 5HT2C) and at other neurotransmitter systems, and MDMA in particular also blocks the serotonin transporter (SERT). 992 I Essential Psychopharmacology apparently be precipitated by a number of environmental stimuli. The psychopharmacological mechanism underlying flashbacks is unknown, but its phenomenology suggests the possibility of a neurochemical adaptation of the serotonin system and its receptors related to reverse tolerance that is incredibly long-lasting. Alternatively, flashbacks could be a form of emotional conditioning embedded in the amygdala and then triggered when a later emotional experience, occurring when one is not taking a hallucinogen, nevertheless revives the memory of experiences that occurred during intoxication. This could precipitate a whole cascade of feelings that occurred during intoxication with a hallucinogen. This is analogous to the types of reexperiencing flashbacks that occur without drugs in patients with posttraumatic stress disorder. Club drugs Phencyclidine and ketamine Phencyclidine (PCP) and ketamine both have actions at glutamate synapses within the reward system (Figure 19-43). They both act as antagonists of NMDA receptors, binding to a site in the calcium channel (see discussion in Chapter 13 and Figures 13-30 and 13-31). Both were originally developed as anesthetics. PCP proved to be unacceptable for this use because it induces a unique psychotomimetic/hallucinatory experience very similar to schizophrenia. The NMDA receptor hypoactivity that is caused by PCP has become a model for the same neurotransmitter abnormalities postulated to underlie schizophrenia (see discussion in Chapter 9 and Figures 9-39 through 9-42). Its structurally and mechanism-related analog ketamine is still used as an anesthetic, but it causes far less of the psychotomimetic/hallucinatory experience. Nevertheless, some people do abuse ketamine, one of the "club drugs" sometimes called "special K." PCP causes intense analgesia, amnesia, and delirium, stimulant as well as depressant actions, staggering gait, slurred speech, and a unique form of nystagmus (i.e., vertical nystagmus). Higher degrees of intoxication can cause catatonia (excitement alternating with stupor and catalepsy), hallucinations, delusions, paranoia, disorientation, and lack of judgment. Overdose can include coma, extremely high temperature, seizures, and muscle breakdown (rhabdomyolysis). Gamma hydroxybutyrate (GHB) This agent is discussed extensively in Chapter 16 as a treatment for narcolepsy/cataplexy. It is sometimes also abused (Figure 19-43). The mechanism of action ofGHB is as an agonist at its own GHB receptors and at GABA-B receptors (illustrated in Figure 16-35). Inhalants Agents such as toluene are thought to be direct releasers of dopamine in the nucleus accumbens. Sexual disorders From a psychopharmacological perspective, the human sexual response can be divided into three phases, each with distinct and relatively nonoverlapping neurotransmitter functions: libido, arousal, and orgasm (Figure 19-44). Libido The first stage, libido, is linked to desire for sex, or sex drive, and is a complex process regulated by neurotransmitters, hormones, and past experiences. Dopamine activity in reward circuitry is thought to playa central role (Figure 19-45). In addition to the projections of Disorders of Reward, Drug Abuse, and Their Treatment I 993 Actions of Club Drugs on Reward Circuits nucleus accumbens PCP ketamine GHB FIGURE 19-43 Actions of club drugs on reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA),site of dopamine cell bodies that receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTAand the nucleus accumbens. Club drugs such as phencyclidine (PCP) and ketamine are antagonists at N-methyl-d-aspartate (NMDA) receptors and thus cause NMDAhypoactivity, which in turn leads to disinhibition of dopamine release. Gamma hydroxybutyrate (GHB), which is an agonist at GHB and GABA-Breceptors, is also sometimes abused. dopamine to the nucleus accumbens emphasized in this chapter, dopamine also projects to the hypothalamus, where it may also have input to the regulation of sexual desire via neurons in the medial preoptic to play an important area (MPOA in Figure role in sexual motivation 19-45). The MPOA in experimental animals, has been shown whereas another area of the hypothalamus, the paraventricular nucleus, may control genital responses and a third area of the hypothalamus, the ventromedial nucleus, may regulate the expression of sexual receptivity (lordosis in animals). Numerous hypothalamic 994 agents positively areas, including I Essential Psychopharmacology regulate estrogen sexual motivation and testosterone, by their dopamine, actions in these as well as various Psychopharmacology Stage One: Desire DA Stage Two: Arousal + melanocortin testosterone estrogen prolactin of Sex NO + + + + NE + melanocortin testosterone estrogen 5HT Stage Three: Orgasm ACh DA 5HT 5HT NE DA NO + + + + + - + +/+/- FIGURE 19-44 Psychopharmacology of sex. The neurotransmitters involved in the three stages of the psychopharmacology of the human sexual response are summarized here. In stage 1, desire, dopamine (DA), melanocortin, testosterone, and estrogen exert a positive influence, while prolactin and serotonin (5HT) have negative effects. In stage 2, arousal correlates with erection in men and genital swelling and lubrication in women. Several neurotransmitters facilitate sexual arousal, including nitric oxide (NO), norepinephrine (NE), melanocortin, testosterone, estrogen, acetylcholine (ACh), and DA. As with desire, 5HT has a negative effect. Stage 3, orgasm, which is associated with ejaculation in men, is inhibited by 5HT and facilitated by NE; DAand NO may have weak positive influences. peptide neurotransmitters such as melanocortin the other hand, is hypothesized This is interesting, prolactin prolactin (Figures to have a negative influence since there is a generally reciprocal 19-44 and 19-45). Prolactin, on 19-44). on sexual desire (Figure relationship between dopamine and (as discussed in Chapter 9; see Figure 9-11). However, the relationship between and sexual dysfunction is not well documented and relatively poorly understood. Serotonin also has a negative influence to its inhibitory influence on dopamine dopamine release is discussed on sexual motivation and desire, presumably due release (Figure 19-44). Serotonergic inhibition of in Chapter 10 and illustrated in Figures 10-21 to 10-25. Arousal The second psychopharmacological stage of the sexual response is arousal (Figure 19-44): arousal of peripheral tissues, that is. In men, that means an erection; in women, that means genital lubrication and swelling. This type of arousal prepares the genitalia for penetration and sexual intercourse. The message of arousal starts in the brain; it is then relayed down the spinal cord and into peripheral autonomic parasympathetic; next, it travels into vascular nerve fibers that are both sympathetic and tissues and finally to the genitalia. Along Disorders of Reward, Drug Abuse, and Their Treatment I 995 Sexual Desire and Reward Circuits nucleus accumbens VTA FIGURE 19-45 Sexual desire and reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA), site of dopamine cell bodies which receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTA and the nucleus accumbens. Dopamine activity in reward circuitry is thought to playa central role in sexual desire. Dopaminergic neurons also project to the hypothalamus, where they may have input to the regulation of sexual desire via neurons in the medial preoptic area (MPOA) and the projections of those neurons to the nucleus accumbens. the way, at least two key neurotransmitters are involved, acetylcholine in the autonomic parasympathetic innervation of the genitalia and nitric oxide, which acts upon the smooth muscle of the genitalia (Figures 19-44 and 19-45). Acetylcholine and nitric oxide both promote erections in men and lubrication and swelling in women. Nitric oxide psychopharmacology Nitric oxide (NO), a gas, is an improbable compound for a neurotransmitter. It is not an amine, amino acid, or peptide; it is not stored in synaptic vesicles or released by exocytosis; and it does not interact with specific receptor subtypes in neuronal membranes; but it is 996 I Essential Psychopharmacology 19-46 Sexual arousal and neurotransmitters.Sexualarousal in peripheralgenitaliais accompaniedby erectionsin men and lubricationand swellingin women. Bothnitricoxide and acetylcholineare regulatorsof these actions. FIGURE Sexual Arousal and Neurotransmitters 00 ACh 0 o® lubrication, NO ~ -------9d . swelling ~ erection "no laughing matter." Specifically, it is not nitrous oxide (N20) or "laughing gas," one of the earliest known anesthetics. Nitric oxide is a far different gas, although the two are often confused. It is NO that is the neurotransmitter, not N20. Incredible as it may seem, NO is a poisonous and unstable gas, a component of car fumes that helps to deplete the ozone layer, yet is also a chemical messenger both in the brain and in blood vessels, including those that control erections of the penis. Yes, there is NO synthesis by neurons and the penis. Certain neurons and tissues possess the enzyme nitric oxide synthetase (NOS), which forms NO from the amino acid I-arginine (Figure 19-47 A). NO then diffuses to adjacent neurons or smooth muscle and provokes the formation of the second messenger cyclic GMP (guanosine monophosphate) by activating the enzyme guanylyl cyclase (GC) (Figure 19-47B). NO is not made in advance, nor is it stored; it seems to be made on demand and released by simple diffusion. Glutamate and calcium can trigger the formation of NO by activating NOS. No, there are no NO receptors. In striking contrast to classic neurotransmitters, which have numerous types and subtypes of membrane receptors on neurons, there are no NO membrane receptors. Rather, the target of NO is iron in the active site of GC (Figure 19-47B). Once NO binds to the iron, GC is activated and cGMP is formed. The action of cGMP is terminated by a family of enzymes known as phosphodiesterases (PDE), of which there are several forms, depending upon the tissue (Figure 19-47C). Yes, there is NO neurotransmitter function. The first known messenger functions for NO were described in blood vessels. By relaxing smooth muscles in blood vessels of the penis, NO can regulate penile erections, allowing blood to flow into the penis. NO also can modulate vascular smooth muscle in cardiac blood vessels and mediate the ability of nitroglycerin to treat cardiac angina. NO is also a key regulator of blood pressure, platelet aggregation, and peristalsis. Its CNS neurotransmitter function remains elusive, but it may be a "retrograde neurotransmitter." That is, since presynaptic neurotransmitters activate postsynaptic receptors, it seems logical that communication in this direction should be accompanied by some form of back talk from the postsynaptic site to the presynaptic neuron. The idea is that NO formation is prompted in postsynaptic synapses by some presynaptic neurotransmitters and then diffuses back to the presynaptic neuron, carrying information in reverse. NO may also be involved in memory formation, neuronal plasticity, and neurotoxicity. The notion of retrograde neurotransmission is introduced in Chapter 3, and the role of NO as a potential retrograde neurotransmitter is illustrated in Figure 3-3. Other neurotransmitters and hormones that affect arousal positively include norepinephrine, melanocortin, testosterone, and estrogen (Figure 19-44). Serotonin has a negative influence on sexual arousal (Figure 19-44). Disordersof Reward,DrugAbuse,and TheirTreatment 997 Nitric Oxide (NO) and Sexual Arousal A. synthesis of NO ~ L-arginine ~~ ~ 00 ~ 0·00 o 0 o o o o nitric oxide synthetase o 00 NO (nitric oxide) 0 00 o En:> 000 B. synthesis of cGM P with sexual arousal ~ ~J'; 00 0 HEME ~ () lubrication, '"+' swelling erection A. /'" _ri CG~ C. enzymatic destruction of cGMP with loss of sexual arousal cGMP ~ FIGURE 19-47A, 8, and C Nitric oxide (NO) and sexual arousal. (A) NO is formed by the enzyme nitric oxide synthetase (NOS), which converts the amino acid I-arginine into NO and I-citrulline. (8) Once formed, NO activates the enzyme guanylyl cyclase (GC) by binding to iron (heme) in the active site of this enzyme. When activated, GC makes a messenger, cGMP (cyclic guanylate monophosphate), which relaxes smooth muscle and performs other physiological functions. In the penis, relaxation of vascular smooth muscle opens blood flow and causes an erection. (C) The action of cGMP is terminated by the enzyme phosphodiesterase, thus ending sexual arousal. In the penis, the type of phosphodiesterase is type V (PDE V). 998 Essential Psychopharmacology Neurotransmitters serotonin ~~ ••• and Orgasm 9 d orgasm ejaculation and orgasm " h"nne .•.•.e}.4:, noreplnep 4:, FIGURE 19-48 Neurotransmitters and orgasm. Orgasm is the third stage of the human sexual response, accompanied by ejaculation in men. Serotonin exerts an inhibitory action on orgasm and norepinephrine a facilitatoryone. Orgasm The third stage of the human sexual response is orgasm (Figure 14-44), accompanied by ejaculation in men. Descending spinal serotonergic fibers exert inhibitory actions on orgasm via 5HT receptors, perhaps 5HT2A and 5HT2C receptors (Figure 19-48). Descending spinal noradrenergic fibers and noradrenergic sympathetic innervation of genitalia facilitate ejaculation and orgasm (Figure 19-44). Dopamine and NO may have weak positive influences on facilitating orgasm (Figure 19-44). Sexual disorders and reward Erectile dysfunction The inability to maintain an erection sufficient for intercourse is called erectile dysfunction (formerly impotence). Up to 20 million men in the United States have this problem to some degree. Another way of stating the problem is that for normal men between 40 and 70 years of age living in the community, only about half do not have some degree of erectile dysfunction (Figure 19-49). The problem gets worse with age (Figure 19-50), since 39 percent of 40-year-olds have some degree of erectile dysfunction (5 percent are completely impotent); but by age 70, two thirds have some degree of erectile dysfunction (and complete impotence triples to 15 percent). The multiple causes of erectile dysfunction include vascular insufficiency, various neurological conditions, endocrine pathology (especially diabetes mellitus but also reproductive hormones and thyroid problems), drugs, local pathology in the penis, and psychological and psychiatric problems. Until recently, psychopharmacologists were not very useful members of the treatment team for patients with erectile dysfunction other than to stop the medications they were prescribing! Effective treatment of "organic" causes of erectile dysfunction until recently was often elusive and usually involved a urological approach, such as prostheses and implants. Disorders of Reward, Drug Abuse, and Their Treatment I 999 Prevalence of Erectile Dysfunction Massachusetts Male Aging Study men aged 40 to 70 years FIGURE 19-49 Prevalence of erectile dysfunction. About half of men between the ages of 40 and 70 experience some degree of erectile dysfunction (impotence). Association between Age and Prevalence of Erectile Dysfunction (ED) Massachusetts Male Aging Study --. §! * C Q ~ c: '-' .9! QJ 80 40 67% 20 57% 600 48% 39% • 40 50 60 • 70 age (y) D complete ED ~ D moderate ED~ III minimal ED FIGURE 19-50 • Association between age and prevalence of erectile dysfunction (ED). In this study of normal men between the ages of 40 and 70, the prevalence of erectile dysfunction increased with age from 39 percent at age 40 to 67 percent at age 70. 1000 I Essential Psychopharmacology Association between Depression and Prevalence of Erectile Dysfunction Massachusetts Male Aging Study 90% 100 -6' OJ c C :c () O JJ .Q u; (tj OJ Q; t5 t5 5; a. '0 ,g 80 40 60 ~20 o mild depression moderate depression severe depression FIGURE 19-51 Associationbetween depressionand prevalenceof erectiledysfunction (ED). Erectile dysfunctionis associatedwith depressionand increasesin frequencyas depressionworsens.Some studies suggestthat over 90 percentof severelydepressed men have erectiledysfunction. The old-fashioned surgical strategy bypasses diseased peripheral nerves and inadequate vascular blood supply to the penis to create erections mechanically and upon demand, but it has serious limitations in terms of patient and partner acceptability. In men who have a "functional" etiology to their erectile dysfunction, the treatment strategy has traditionally taken a psychodynamic and behavioral approach, with attention to partners and functional disorders, psychoeducation, lifestyle changes, and, where appropriate, starting (or stopping) psychotropic drugs to treat associated disorders. The typical case of erectile dysfunction, however, is due to neither a single "organic" cause nor a single "functional" cause but usually involves some combination of problems, including use of alcohol, smoking, diabetes, hypertension, antihypertensive drugs, psychotropic drugs, partner problems, performance anxiety, problems with self-esteem, and psychiatric disorder, especially depression. The topic of erectile dysfunction has become increasingly important in psychopharmacology, not only because there are several psychotropic drugs that cause it but also because of the strikingly high incidence of erectile dysfunction in several common psychiatric disorders. For example, some studies show that more than 90 percent of men with severe depression have moderate to severe erectile dysfunction (Figure 19-51). Another reason for the importance of this topic in psychopharmacology is that several effective and simple psychopharmacological treatments based upon NO physiology and pharmacology are now available for men with erectile dysfunction. Disordersof Reward,DrugAbuse,and TheirTreatment I 1001 Normal Erectile Function o o o o o ® 0 ® ® 0 \ o 0 @ @ 0 FIGURE 19-52 Normal erectile function. 'l Under normal conditions, when young, healthy men are sexually aroused, nitric oxide causes cGMP to accumulate, and cGMP causes smooth muscle relaxation, resulting in a physiological erection (indicated here by an inflated balloon). The erection is sustained long enough for sexual intercourse, and then phosphodiesterase V (PDE V) metabolizes cGMp, reversing the erection (indicated here by a pin ready to prick the balloon). Psychopharmacology of erectile dysfunction Normally, the desire to have sex is a powerful message sent from the brain down the spinal cord and through peripheral nerves to smooth muscle cells in the penis, triggering them to produce plenty of NO to form all the cyclic GMP necessary to create an erection (Figure 19-52). The cyclic GMP lasts long enough for sexual intercourse to occur, but then phosphodiesterase (type V in the penis) eventually breaks down the cGMP (shown earlier in Figure 19-47C) and the erection is lost (called detumescence). However, if you smoke, eat to the point of obesity, have elevated blood glucose and elevated blood pressure, your peripheral nervous system "wires" may not respond adequately to the "let's have sex" signal from the brain (i.e., neurological innervation of the penis is rendered faulty, usually by diabetes) (Figure 19-53). Furthermore, there may not be much pressure in the plumbing (i.e., atherosclerosis of the arterial supply of the penis from hypertension and hypercholesterolemia) when cGMP says "relax the smooth muscle and let the blood flow into the penis." In these cases, the desire to have sex is there, but the signal cannot get through, so insufficient cGMP is formed and therefore no erection occurs (Figure 19-53). Similarly, for a depressed patient who has the desire for sex, there is a general shutdown of neurotransmitter systems centrally and peripherally and the inability to become aroused (Figure 19-53). Fortunately, there is a way to compensate for inadequate amounts of cGMP being formed. That compensation is to slow the rate of destruction of that cGMP that is formed. This is done by inhibiting the enzyme that normally breaks down cGMP in the penis, namely phosphodiesterase type V (Figure 19-54). There are now three inhibitors of this enzyme available: sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) (Figure 19-54). These phosphodiesterase type V inhibitors will stop cGMP destruction for a time ranging from a few hours to a few days and allow the levels of cGMP to build up; therefore 1002 Essential Psychopharmacology Erectile Dysfunction (ED) o o o o o @0 ® ® 0 \~ o 0 @ FIGURE 19-53 0 'l@ Erectile dysfunction. When a man has diabetes or hypertension or if he smokes, uses alcohol, takes prescription drugs, or is depressed, there is a good chance that not enough of a signal of sexual desire will be able to get through his peripheral nerves and arteries to produce sufficient amounts of cGMP to cause an erection. This leads to erectile dysfunction. Treatment of Erectile Dysfunction (ED) o o o o o ® 0 ® ® FIGURE 19-54 0 ®\~ o 0 0 ® 'l Treatment of erectile dysfunction. Phosphodiesterase V (PDE V) inhibitors are able to compensate for faulty signals through the peripheral nerves and arteries that produce insufficient amounts of cGMP to cause or sustain an erection. PDE V inhibitors do this by allowing cGMP to build up, since PDE V can no longer destroy cGMP for a few hours to a few days. This is indicated by a patch on the balloon in the figure. The result is that normally inadequate nerves and arteries signaling cGMP formation are now sufficient to inflate the balloon and therefore an erection can occur and sexual intercourse is possible until the drug wears off a few hours to a few days later. Disorders of Reward, Drug Abuse, and Their Treatment 1003 an erection can occur even though the "wires" and "plumbing" are still faulty (Figure 19-53). Interestingly, these agents work only if the patient is mentally interested in sex and attempts to become aroused, so that at least weak signals are sent to the penis (i.e., it does not work during sleep). Smooth muscle relaxation is thus the key element in attaining an erection. Administration of prostaglandins can also relax penile smooth muscle and elicit erections in a manner that mimics typical physiological mechanisms. Thus, intrapenile injection of the prostaglandin alprostadil produces erections not only in men with organic causes of impotence but also in those with functional causes and even in the common situation of multifactorial causes. Limitations of this somewhat masochistic approach include the unacceptability of self-injection, lack of spontaneity, and the possibility of too much of a good thing, namely a prolonged and painful erection, or priapism. Prostaglandin administration will cause an erection whether the man is mentally aroused or not. Other drugs can affect sexual arousal, including SSRIs or SNRIs in some patients. Some of these agents may inhibit NOS directly and thus can cause erectile dysfunction. On the other hand, some dopaminergic agents might boost NOS, and for this reason pro-dopaminergic agents may be useful not only in enhancing desire but also in enhancing arousal. Anticholinergic agents can interfere directly with arousal and cause erectile dysfunction. Thus, those antipsychotics, tricyclic antidepressants, and other drugs with anticholinergic properties can cause erectile dysfunction. Hypoactive sexual desire disorder (HSDD) Another disorder of sexual function is decreased libido, lack of sexual motivation, and decreased sexual fantasies, known as hypoactive sexual desire disorder (HSDD). This is a controversial concept, because it can be difficult to separate a chronic and disabling condition from common transient alterations in sexual behavior related to interpersonal problems, life stress, and just common fatigue, overwork, and sleep deprivation that are part of living in the modern world. Now that there are potential treatments on the horizon, is it possible that HSDD is just a "corporate sponsored creation of a new disease"? Furthermore, decreased libido is often part of major depressive disorder (see discussions in Chapters 11 and 12 and Figures 11-45, 11-55, and 12-124 through 12-126), so is it possible that decreased libido is more likely to be a residual symptom of a major depressive episode that has not gone into remission rather than an independent clinical entity (Figure 19-55)? Finally, HSDD is often considered to be mostly a disorder of females, perhaps especially by men, so is it a gender relationship issue of men rather than a true form of sexual dysfunction in women? Many women report reduction of sexual desire with the duration of a relationship, and some may have lost interest in their partner but may still feel like having sex with the guy next door. Such issues are not likely to be resolved by taking drugs to enhance sexual desire, and answers to these various questions may be forthcoming as further research is done on the symptom of decreased libido. Nevertheless, it is already clear that certain hormones and drugs can increase sexual desire in those who complain of having too little of it. Like many of the disorders discussed in this text, to the extent that the core symptoms of decreased libido and decreased sexual fantasies define HSDD, there are frequently many associated nondiagnostic symptoms that are equally important to assess and treat (Figure 19-55). These include various symptoms of major depression, not just depressed mood and decreased libido itself but also change in appetite and weight (self-image and body-image problems can interfere secondarily with sexual desire); apathy, loss of interest and lack of 1004 I Essential Psychopharmacology vasomotor symptoms FIGURE 19-55 Hypoactive sexual desire disorder (HSDD). HSDD is a disorder of sexual function characterized by decreased libido and decreased sexual fantasies. In addition, there are many associated nondiagnostic symptoms, as shown here. These include various symptoms of major depression, vasomotor symptoms in perimenopausal women, hypoestrogen and/or hypotestosterone states in women, and hypotestosterone states in men. experiencing pleasure globally and not just with sex; lack of motivation to do many things, not just sexual intercourse; and of course fatigue, which may be the greatest antiaphrodesiac known (Figure 19-55). Also, a number of other conditions may be associated with HSDD, including vasomotor symptoms in perimenopausal women, discussed extensively in Chapter 12 and illustrated in Figures 12-104, 12-106 and 12-124 through 12-126. Hypoestrogen and hypotestosterone states in women and hypotestosterone states in men can also be associated with lack of sexual interest as one of the symptoms (Figure 19-55). Thus the symptom of lack of sexual interest requires in-depth evaluation and then constructing a proper diagnosis (Figure 19-55). The strategy then is to deconstruct the various symptoms of the patient's syndrome (e.g., those listed in Figure 19-55) and match them to hypothetically malfunctioning brain circuits (Figure 19-56). Knowing the neurotransmitters (and hormones) that affect neurotransmission in these circuits provides a psychopharmacological rationale for selecting and combining treatments to eliminate the patient's symptoms. Note in Figure 19-56 that the great majority of symptoms associated with HSDD (shown in Figure 19-55) are linked to the nucleus accumbens, the critical area of the brain that regulates reward (Figures 19-2, 19-3, and 19-45). Although there are no approved treatments for HSDD, several approaches targeting neurotransmitters and hormones in reward circuitry are being tested in clinical trials. The notion is that the low sexual desire ofHSDD is linked to low functioning of dopaminergic reward neurons in the mesolimbic pathway (Figure 19-57 A). Indeed, anecdotal observations document that some patients taking levodopa or dopamine agonists for Parkinson's disease experience increased sex drive, as do some patients taking the pro-dopaminergic antidepressant and NDRI bupropion. Testosterone may enhance sexual interest by actions on neurons in the hypothalamus and boost the ability of dopamine to act in the hypothalamus. Disorders of Reward, Drug Abuse, and Their Treatment I 1005 Some Key HSDD Symptoms Hypothetically interests apathy pleasure libido fatigue euphoria reward motivation sexual arousal drug abuse Linked to Specific Brain Regions physicalfatigue depressed mood estrogen/testosterone disturbances appetite/weight vasomotorsymptoms delayed orgasm/anorgasmia ejaculatory disturbances FIGURE 19-56 Matching hypoactive sexual desire disorder (HSDD) symptoms to circuits. Alterations in neurotransmission within each of the brain regions shown here can be hypothetically linked to the various symptoms associated with HSDD. Functionality in each brain region may be associated with a different constellation of symptoms. PFC: prefrontal cortex; BF: basal forebrain; S: striatum; NA: nucleus accumbens; T: thalamus; HY: hypothalamus; A: amygdala; H: hippocampus; NT: brainstem neurotransmitter centers; SC: spinal cord; C: cerebellum. In fact, testosterone has shown positive results in women given low doses transdermally, but concerns about long-term safety led the FDA to withhold approval of this approach pending more safety studies. One novel approach melanocortin receptors to HSDD is to administer in the hypothalamus (Figure a peptide 19-57B). lanotide is an agonist at melanocortin MC3 and MC4 receptors in the hypothalamus increases sexual behavior intranasally Specifically, that acts on the drug breme- receptors, and stimulating these in animals, boosts the actions of DA in hypothalamic areas such as the medial preoptic area (MPOA) (see Figure 19-57B), and also shows preliminary evidence of efficacy in women with HSDD (and also in men with erectile dysfunction). raise blood pressure. Concerns have arisen, however, about the ability of this drug to Another novel approach to HSDD is the serotonergic agent flibanserin, which has shown preliminary evidence of efficacy in women with HSDD. Flibanserin acts as a norepinephrine of5HT1A and dopamine disinhibitor (NDDI) agonism, plus 5HT2A and 5HT2C by means of its pharmacological properties antagonism (Figure 19-57B). NDDI action due to 5HT2C antagonism is discussed extensively in Chapter 12 and illustrated in Figure 12-25. The enhancement of dopamine release by combining 5HT2C (and 5HT2A) antagonism with agonist actions at 5HT1A receptors is discussed in Chapter 10 and illustrated in Figure 10-21; it is also discussed in Chapter 12 and illustrated in Figures 12-61 through 1264. Flibanserin increases dopamine (and norepinephrine) release and also reduces serotonin release, properties that would enhance when these actions occur in the MPOA 1006 Essential Psychopharmacology reward and hypothetically and nucleus accumbens increase sexual motivation (Figure 19-57B). Ongoing HSDD: Low Sexual Desire, Low Dopamine nucleus accumbens "I have a headache" MPOA -,1tDA · · ·· raphe 5HT1A : -..••". DA • neuron VTA 5HT 5HT ", ~t46c'" GABA ZI MPOA = medial pre optic area ZI = zona incerta I normal . baseline overactivation hypoactivation A FIGURE 19-57A Hypoactive sexual desire disorder (HSDD): low dopamine? Low sexual desire in HSDD is believed to be due to hypoactivity of mesolimbic dopaminergic neurons (depicted here by the blue color and dashed lines of the neuron). research will determine whether flibanserin has sufficient efficacy and safety in HSDD to possibly become the first approved treatment for this condition. Compulsive sexual behavior A number of conditions linked to sexual activity of various sorts have been categorized as disorders of impulsivity (Table 19-5). Hypothetically, some of these conditions could be linked to abnormal activity of reward circuits (Figure 19-2), analogous to an addiction, where there is deficient descending inhibitory influence from the reflective reward system in the prefrontal cortex (Figure 19-3) to stop the expression of abnormal sexual drives arising from the reactive reward system of the VTA and amygdala (Figure 19-4). These concepts are controversial if novel, and therapeutic approaches targeting neurotransmitters in reward circuitry (Figures 19-5 through 19-8) may eventually provide relief for some of these disorders (Table 19-5). Disorders of Reward, Drug Abuse, and Their Treatment I 1007 Treatment of HSDD: Raising Dopamine Improves Sexual Desire nucleus accumbens MPOA raphe __:'.1 .. 5HT "'\ neuron.- 5J:1T1 A ":; , c. VTA ZI flibanserin MPOA = medial pre optic area ZI = zona incerta I normal baseline ~ overactivation hypoactivation B FIGURE 19-578 Treatment of hypoactive sexual desire disorder (HSDD) by raising dopamine. Potential treatments for HSDD include agents that increase dopaminergic neurotransmission in the nucleus accumbens. This may be achieved with bremelanotide, which is an agonist at melanocortin 3 and 4 (MC3 and MC4) receptors in the medial preoptic area (MPOA) of the hypothalamus, or by flibanserin, which is a 5HTlA agonist and a 5HT2A and 5HT2C antagonist. Eating disorders Eating disorders and reward circuits Should obesity be included as a brain disorder? Did my receptors make me eat it? Obesity is a complex disorder, with lifestyles, diet, and exercise playing major roles in twenty-first century society. Certainly there is an ongoing epidemic of obesity and metabolic disorder in society today; this is discussed in Chapter 10 in relation to antipsychotic drugs and illustrated in Figures 10-59 through 10-69. Chapter 10 also discusses the potential roles of genes associated with various mental illnesses and drugs used to treat mental illnesses as additional risk factors for obesity, and ultimately It is also possible that some forms of obesity drive for food, mediated 1008 by reward Essential Psychopharmacology circuitry, cardiometabolic disorders. are driven by an excessive and as such might motivational be considered as mental TABLE 19-5 Psychopharmacologyand sexualdisorder Erectile dysfunction (ED) Hypoactive sexual desire disorder (HSDD) Anorgasmial ejaculatory delay Premature ejaculation Sexual pain disorders SSRI/SNRI -induced sexualdysfunctions Sexual "addictions"- impulsivity/compulsivitydisorders: Paraphilias Exhibitionism Fetishism Frotteurism Pedophilia Sexual sadism Sexual masochism Transvestic fetishism Voyeurism Compulsive cruising and multiple partners Compulsive fixation on an unattainable partner Compulsive autoeroticism Compulsive use of erotica Compulsive use of the internet Compulsive multiple love relationships Compulsive sexualityin a relationship disorders. Can you be addicted to food with compulsive consumption and the inability to refrain from eating despite the desire to do so? Can you be addicted to carbohydrates or your "sugar fix?" Are high-fat foods "comfort foods" that relieve craving and cause pleasure because they are addicting? These symptoms associated with obesity, overeating, and binge eating in many patients are remarkably similar to the addictions to various drugs described in this chapter. A hypothetical if oversimplified idea for how certain eating disorders could be linked to reward circuits is shown in Figure 19-58, with dopamine projections not only to the nucleus accumbens but also to the mammillary nucleus of the hypothalamus, an area of the hypothalamus that exerts important regulatory control of eating in animals. This region projects to nucleus accumbens as well, where it may regulate the motivation to eat (and addiction to food?). Current research is attempting to clarifY the role of a long list of other key regulators of hypothalamic activity in eating: leptin, ghrelin, anandamide, neurotensin, CRF, cholecystokinin, insulin, glucagon, calcitonin, amylin, bonbesin, somatostatin, cytokines, melanocortin, orexin, dynorphin, beta endorphin, galanin, neuropeptide Y and many other hormones, neurotransmitters and hypothalamic peptides. The roles of hypothalamic serotonin actions, particularly at 5HT2C receptors, and hypothalamic histamine actions, particularly at HI receptors, are discussed in Chapter 10 and illustrated in Figure 10-59. Treatments for compulsive eating, obesity, and "food addiction" The prevalence and morbidity of obesity are sufficiently vast that it is important if not urgent to develop therapeutic interventions. It is possible that some patients could benefit from approaches that target hypothalamic and mesolimbic reward circuits, since obesity Disordersof Reward,DrugAbuse,and TheirTreatment I 1009 Eating, Hunger, and Reward Circuits nucleus accumbens VTA FIGURE 19-58 Eating, hunger, and reward circuits. Shown here is the reactive reward system consisting of the ventral tegmental area (VTA) , site of dopamine cell bodies that receives many neurotransmitter projections; the nucleus accumbens, to which dopaminergic neurons project; and the amygdala (far left), which has connections with both the VTA and the nucleus accumbens. In addition, dopamine projections extend to the mammillary nucleus (MAM) of the hypothalamus, an area important for regulatory control of eating; projections from these regions themselves extend to the nucleus accumbens. Thus the circuitry of hunger is interconnected with the circuitry for reward. may not always be just a metabolic disorder but, in some cases, a disorder of reward circuits or even an addiction. Current drugs of abuse, especially stimulants and nicotine, reduce appetite. Others, such as marijuana, actually stimulate appetite, leading to the use of the cannabinoid CBl antagonist for the treatment of obesity. As mentioned earlier, this agent is approved in some countries but not in the United States. Approved stimulants for obesity, including the SNRI sibutramine, have fallen into relative disrepute given their lack of long-term efficacy in most patients plus the risk of hypertension and the toxicity scare caused by the amphetamine derivative fenfluramine in the recent past. Orlistat, now available without prescription, inhibits fat absorption and works peripherally and not on reward circuitry 1010 I Essential Psychopharmacology except to the extent that it causes an aversive response to eating fatty foods (diarrhea and flatus). It is not highly utilized or highly palatable to many patients. Fluoxetine is approved for bulimia and acts perhaps in part to suppress appetite via its 5HT2C antagonist properties (see Figure 12-25). Other agents active at 5HT2C sites, including both agonists (e.g., GSK 875167 and others) and antagonists (see the list at the end of Chapter 10 on new treatments for schizophrenia) are also in testing for obesity. The anticonvulsants topiramate and zonisamide and the ADHD drug and norepinephrine reuptake inhibitor atomoxetine have anecdotally been associated with weight loss in some patients and are now in testing for obesity. Some medications approved for diabetes may hold promise for the treatment of obesity, including metformin and the injectable peptide pramlintide (Symlin; discussed in Chapter 10). Another novel agent is Axokine, or ciliary neurotrophic factor, which is in testing for obesity, since it seems to cause weight loss in humans. Cholecystolinin agonists (e.g., GSK 181771) and other agents active at various peptide receptors, including bremelanotide (MC3 and MC4 agonist discussed above for treatment of HSDD and illustrated in Figure 19-57B) are also in testing for obesity. Some analysts estimate that there are actually hundreds of agents in testing for obesity in the hope that some therapeutic intervention can be found for this epidemic. Some of the approaches target reward circuitry (Figure 12-58) and approach obesity as a disorder of reward, analogous to an addiction. Other impulse-control disorders A number of other conditions have been linked to reward circuitry and have been conceptualized as addictions. This includes borderline personality disorder, compulsive gambling, kleptomania, pyromania, compulsive shopping, and other related conditions. Whether these will prove to be disorders of reward and whether they will prove treatable by approaching them as addictions remains a topic of intense current interest and research. Summary This chapter discussed the psychopharmacology of reward and the brain circuitry that regulates reward. We have attempted to explain the psychopharmacological mechanisms of action of various drugs of abuse, from nicotine to alcohol, and also opiates, stimulants, sedative hypnotics, marijuana, hallucinogens, and club drugs. In the case of nicotine and alcohol, various novel psychopharmacological treatments are discussed, including the alpha 4 beta 2 selective nicotine partial agonist (NPA) varenicline for smoking cessation and naltrexone and acamprosate for alcohol dependence. For each of the drug classes explored, their hypothetical actions upon mesolimbic reward circuitry are explained. Disorders of sexual function hypothetically linked to dysregulation of reward mechanisms in this same circuitry are also explored. Finally, a number of disorders are discussed that are not recognized substance abuse disorders but may be forms of addiction, including obesity, gambling, and other related conditions. Disorders of Reward, Drug Abuse, and Their Treatment I 1011