Case Study

A retired accountant developed a tremor and slowing of movements and was diagnosed with Parkinson’s disease at age 67. At that time, his neurologist prescribed levodopa to restore dopamine levels. A couple of years later, motor symptoms start to fluctuate and the dopamine receptor agonist ropinirole is added to his treatment.* A few months later, he develops a strong interest in gambling, first buying lottery tickets and then visiting a casino almostevery day. He conceals his gambling activity until he has lost more than $100,000. When he came for a consultation 5 weeks ago, ropinirole was replaced with monoamine oxidase inhibitor therapy. He now reports that his interest in gambling has disappeared. What may be the link between the dopamine agonist treatment and gambling addiction?

*The treatment of Parkinson's disease is discussed in Chapter 28.

Drugs of Abuse: Introduction

Drugs are abused (used in ways that are not medically approved) because they cause strong feelings of euphoria or alter perception. However, repetitive exposure induces widespread adaptive changes in the brain. As a consequence drug use may become compulsive—the hallmark of addiction.

Basic Neurobiology of Drug Abuse

Dependence versus Addiction

Recent neurobiologic research has led to the conceptual and mechanistic separation of "dependence" and "addiction." The older term "physical dependence" is now denoted as dependence, whereas "psychological dependence" is more simply called addiction.

Every addictive drug causes its own characteristic spectrum of acute effects, but all have in common that they induce strong feelings of euphoria and reward. With repetitive exposure, addictive drugs induce adaptive changes such as tolerance (ie, escalation of dose to maintain effect). Once the abused drug is no longer available, signs of withdrawal become apparent. A combination of such signs, referred to as the withdrawal syndrome, defines dependence. Dependence is not always a correlate of drug abuse—it can also occur with many classes of nonpsychoactive drugs, eg, sympathomimetic vasoconstrictors and bronchodilators, and organic nitrate vasodilators. Addiction, on the other hand, consists of compulsive, relapsing drug use despite negative consequences, at times triggered by cravings that occur in response to contextual cues (see Animal Models in Addiction Research). Although dependence invariably occurs with chronic exposure, only a small percentage of subjects develop a habit, lose control, and become addicted. For example, very few patients who receive opioids as analgesics desire the drug after withdrawal. And only one person out of six becomes addicted within 10 years of first use of cocaine. Conversely, relapse is very common in addicts after a successful withdrawal when, by definition, they are no longer dependent.

Addictive Drugs Increase the Level of Dopamine: Reinforcement

To understand the long-term changes induced by drugs of abuse, their initial molecular and cellular targets must be identified. A combination of approaches in animals and humans, including functional imaging, has revealed the mesolimbic dopamine system as the prime target of addictive drugs. This system originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brain stem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex (Figure 32–1). Most projection neurons of the VTA are dopamine-producing neurons. When the dopamine neurons of the VTA begin to fire in bursts, large quantities of dopamine are released in the nucleus accumbens and the prefrontal cortex. Early animal studies pairing electrical stimulation of the VTA with operant responses (eg, lever pressing) that result in strong reinforcement established the central role of the mesolimbic dopamine system in reward processing. Direct application of drugs into the VTA also acts as a strong reinforcer, and systemic administration of drugs of abuse causes release of dopamine.

As a general rule, all addictive drugs activate the mesolimbic dopamine system. The behavioral significance of this increase of dopamine is still debated. An appealing hypothesis is that mesolimbic dopamine codes for the difference between expected and actual reward and thus constitutes a strong learning signal (see The Dopamine Hypothesis of Addiction).

Since each addictive drug has a specific molecular target that engages distinct cellular mechanisms to activate the mesolimbic system, three classes can be distinguished: A first group binds to G_io protein-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets the dopamine transporter (Table 32–1 and Figure 32–2). G protein-coupled receptors (GPCRs) of the G_io family inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. In the VTA, the action of these drugs is preferentially on the -aminobutyric acid (GABA) neurons that act as local inhibitory interneurons. Addictive drugs that bind to ionotropic receptors and ion channels can have combined effects on dopamine neurons and GABA neurons, eventually leading to enhanced release of dopamine. Finally, addictive drugs that interfere with monoamine transporters block reuptake or stimulate nonvesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures. Since neurons of the VTA also express somatodendritic transporters, which normally clear dopamine released by the dendrites, class III drugs also increase dopamine level in the VTA. Although drugs of this class also affect transporters of other monoamines (norepinephrine, serotonin), it is the action on the dopamine system that remains central for addiction. This is consistent with the observations that antidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use.

Dependence: Tolerance & Withdrawal

With chronic exposure to addictive drugs, the brain shows signs of adaptation. For example, if morphine is used at short intervals, the dose has to be progressively increased over the course of several days to maintain rewarding or analgesic effects. This phenomenon is called tolerance. It may become a serious problem because of increasing side effects—eg, respiratory depression—that do not show much tolerance and may lead to fatalities associated with overdose.

Tolerance to opioids may be due to a reduction of the concentration of a drug or a shorter duration of action in a target system (pharmacokinetic tolerance). Alternatively, it may involve changes of -opioid receptor function (pharmacodynamic tolerance). In fact, many -opioid receptor agonists promote strong receptor phosphorylation that triggers the recruitment of the adaptor protein -arrestin, causing G proteins to uncouple from the receptor and to internalize within minutes (see Chapter 2). Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit -arrestins and fails to promote receptor internalization. Conversely, other agonists that drive receptor internalization very efficiently induce only modest tolerance. Based on these observations, it has been hypothesized that desensitization and receptor internalization actually protect the cell from overstimulation. In this model, morphine, by failing to trigger receptor endocytosis, disproportionally stimulates adaptive processes, which eventually cause tolerance. Although the molecular identity of these processes is still under investigation, they may be similar to the ones involved in withdrawal (see below).

Adaptive changes become fully apparent once drug exposure is terminated. This state is called withdrawal and is observed to varying degrees after chronic exposure to most drugs of abuse. Withdrawal from opioids in humans is particularly strong (described below). Studies in rodents have added significantly to our understanding of the neural and molecular mechanisms that underlie dependence. For example, signs of dependence, as well as analgesia and reward, are abolished in knockout mice lacking the -opioid receptor, but not in mice lacking other opioid receptors (, ). Although activation of the -opioid receptor initially strongly inhibits adenylyl cyclase, this inhibition becomes weaker after several days of repeated exposure. The weaning of the inhibition of adenylyl cyclase is due to a counter-adaptation of the enzyme system during exposure to the drug, which results in overproduction of cAMP during subsequent withdrawal. Several mechanisms exist for this adenylyl cyclase compensatory response, including up-regulation of transcription of the enzyme. Increased cAMP concentrations in turn strongly activate the transcription factor cyclic AMP response element binding protein (CREB), leading to the regulation of downstream genes. Of the few such genes identified to date, one of the most interesting is the gene for the endogenous opioid ligand dynorphin. During withdrawal, neurons of the nucleus accumbens produce high levels of dynorphin, which is then co-released with GABA onto the projection neurons of the VTA (Figure 32–3). These cells express opioid receptors on their synaptic terminals and on the dendrites. As a consequence, they are inhibited and dopamine release is reduced. This mechanism exemplifies the adaptive processes engaged during dependence and may underlie the intense dysphoria typically observed during withdrawal.

Addiction: A Disease of Maladaptive Learning

Addiction is characterized by a high motivation to obtain and use a drug despite negative consequences. With time, drug use becomes compulsive ("wanting without liking"). Addiction is a recalcitrant, chronic, and stubbornly relapsing disease that is very difficult to treat.

The central problem is that even after successful withdrawal and prolonged drug-free periods, addicted individuals have a high risk of relapsing. Relapse is typically triggered by one of the following three conditions: reexposure to the addictive drug, stress, or a context that recalls prior drug use. It appears that when paired with drug use, a neutral stimulus may undergo a switch and motivate ("trigger") addiction-related behavior. This phenomenon may involve synaptic plasticity in the target nuclei of the mesolimbic projection (eg, nucleus accumbens). Several recent studies suggest that the recruitment of the dorsal striatum is responsible for the compulsion. This switch may depend on synaptic plasticity in the nucleus accumbens of the ventral striatum, where mesolimbic dopamine afferents and cortical glutamatergic afferents converge. If dopamine release codes for the prediction error of reward (see The Dopamine Hypothesis of Addiction), pharmacologic stimulation of the mesolimbic dopamine systems will generate an unusually strong learning signal. Unlike natural rewards, addictive drugs continue to increase dopamine even when reward is expected. Such overriding of the prediction error signal may eventually be responsible for the usurping of memory processes by addictive drugs.

The involvement of learning and memory systems in addiction is also suggested by clinical studies. For example, the role of context in relapse is supported by the report that soldiers who became addicted to heroin during the Vietnam War had significantly better outcomes when treated after their return home, compared with addicts who remained in the environment where they had taken the drug. In other words, cravings may recur at the presentation of contextual cues (eg, people, places, or drug paraphernalia). Current research therefore focuses on the effects of drugs on associative forms of synaptic plasticity, such as long-term potentiation (LTP), which underlie learning and memory (see Synaptic Plasticity & Addiction).

Non–substance-dependent disorders, such as pathologic gambling and compulsive shopping, share many features of addiction. Several lines of arguments suggest that they also share the underlying neurobiologic mechanisms. This conclusion is supported by the clinical observation that, as an adverse effect of dopamine agonist medication, patients with Parkinson's disease may become pathologic gamblers (see Case Study). Others patients may develop a habit for recreational activities, such as shopping, eating compulsively, or becoming excessively involved in sexual activity (hypersexuality). Although large-scale studies are not yet available, an estimated 1 of 7 parkinsonian patients develops an addiction-like behavior when receiving dopamine agonists.

Large individual differences exist also in vulnerability to substance-related addiction. Whereas one person may become "hooked" after a few doses, others may be able to use a drug occasionally during their entire lives without ever having difficulty in stopping. Even when dependence is induced with chronic exposure, only a small percentage of dependent users progress to addiction. Recent studies in rats suggest that impulsivity may be a crucial trait that represents a risk for addiction. The transition to addiction is determined by a combination of environmental and genetic factors. Heritability of addiction, as determined by comparing monozygotic with dizygotic twins, is relatively modest for cannabinoids but very high for cocaine. It is of interest that the relative risk for addiction (addiction liability) of a drug (Table 32–1) correlates with its heritability, suggesting that the neurobiologic basis of addiction common to all drugs is what is being inherited. Further genomic analysis indicates that only a few alleles (or perhaps even a single recessive allele) need to function in combination to produce the phenotype. However, identification of the genes involved remains elusive. Although some substance-specific candidate genes have been identified (eg, alcohol dehydrogenase), future research will also focus on genes implicated in the neurobiologic mechanisms common to all addictive drugs.

Nonaddictive Drugs of Abuse

Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissociative anesthetics (Table 32–1). Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin5-HT_2A receptor in the prefrontal cortex, enhancing glutamatergic transmission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of different modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feeling of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibition of glutamate receptors of the N -methyl-D-aspartate (NMDA) type.

The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. In fact, animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Concurrent effects on both thalamocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabinoids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presynaptic inhibition of GABA release.

Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.

Basic Pharmacology of Drugs of Abuse

Since all addictive drugs increase dopamine concentrations in target structures of the mesolimbic projections, we classify them on the basis of their molecular targets and the underlying mechanisms (Table 32–1 and Figure 32-2). The first group contains the opioids, cannabinoids, -hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through G_io protein-coupled receptors. The second group includes nicotine, alcohol, the benzodiazepines, dissociative anesthetics, and some inhalants, which interact with ionotropic receptors or ion channels. The last group comprises cocaine, amphetamines, and ecstasy, which all bind to monoamine transporters. The nonaddictive drugs are classified using the same criteria.

Drugs That Activate G_lo-Coupled Receptors

Opioids

Although opioids may have been the first drugs to be abused (preceding stimulants), they are still among the most commonly used for nonmedical purposes.

Pharmacology & Clinical Aspects

As described in Chapter 31, opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the -, -, and -opioid receptors. Although all three receptors couple to inhibitory G proteins (ie, they all inhibit adenylyl cyclase), they have distinct, sometimes even opposing effects, mainly because of the cell type-specific expression throughout the brain. In the VTA, for example, -opioid receptors are selectively expressed on GABA neurons (which they inhibit), whereas -opioid receptors are expressed on and inhibit dopamine neurons. This may explain why -opioid agonists cause euphoria, whereas agonists induce dysphoria.

In line with the latter observations, the rewarding effects of morphine are absent in knockout mice lacking receptors but persist when either of the other opioid receptors are ablated. In the VTA, opioids cause an inhibition of GABAergic inhibitory interneurons, which leads eventually to a disinhibition of dopamine neurons.

The most commonly abused opioids include morphine, heroin (diacetylmorphine, which is rapidly metabolized to morphine), codeine, and oxycodone. Meperidine abuse is common among health professionals. All of these drugs induce strong tolerance and dependence. The withdrawal syndrome may be very severe (except for codeine) and includes intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, and fever. Beyond the withdrawal syndrome, which usually lasts no longer than a few days, individuals who have received opioids as analgesics only rarely develop addiction. In contrast, when taken for recreational purposes, opioids are highly addictive. The relative risk of addiction is 4 out of 5 on a scale of 1 = nonaddictive, 5 = highly addictive.

Treatment

The opioid antagonist naloxone reverses the effects of a dose of morphine or heroin within minutes. This may be life-saving in the case of a massive overdose (see Chapters 31 and 59). Naloxone administration also provokes an acute withdrawal (precipitated abstinence) syndrome in a dependent person who has recently taken an opioid.

In the treatment of opioid addiction, a long-acting opioid (eg, methadone, buprenorphine) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. Using a partial agonist (buprenorphine) and the much longer half-life (methadone and buprenorphine) may also have some beneficial effects (eg, weaker drug sensitization, which typically requires intermittent exposures), but it is important to realize that abrupt termination of methadone administration invariably precipitates a withdrawal syndrome; that is, the subject on substitution therapy remains dependent. Some countries (eg, Switzerland, Netherlands) even allow substitution of heroin by heroin. A follow-up of a cohort of addicts who receive heroin injections in a controlled setting and have access to counseling indicates that addicts under heroin substitution have an improved health status and are better integrated in society.

Cannabinoids

Endogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors. These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA. Because of such backward signaling, endocannabinoids are called retrograde messengers. In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission and may contribute to the induction of synaptic plasticity during learning and memory formation.

Exogenous cannabinoids, eg in marijuana , include several pharmacologically active substances including ⁹-tetrahydrocannabinol (THC) , a powerful psychoactive substance. Like opioids, THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the VTA. The half-life of THC is about 4 hours. The onset of effects of THC after smoking marijuana occurs within minutes and reaches a maximum after 1–2 hours. The most prominent effects are euphoria and relaxation. Users also report feelings of well-being, grandiosity, and altered perception of passage of time. Dose-dependent perceptual changes (eg, visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and, in rare cases following the use of very high doses, may result in visual hallucinations, depersonalization, and frank psychotic episodes. Additional effects of THC, eg, increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics. The justification of medicinal use of marijuana was comprehensively examined by the Institute of Medicine (IOM) of the National Academy of Sciences in its 1999 report, Marijuana & Medicine. This continues to be a controversial issue, mainly because of the fear that cannabinoids may serve as a gateway to the consumption of "hard" drugs or cause schizophrenia in individuals with a predisposition.

Chronic exposure to marijuana leads to dependence, which is revealed by a distinctive, but mild and short-lived, withdrawal syndrome that includes restlessness, irritability, mild agitation, insomnia, nausea, and cramping. The relative risk for addiction is 2.

The synthetic ⁹-THC analog dronabinol is a Food and Drug Administration (FDA)-approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial ⁹-THC analog, was recently reintroduced in the USA for adjunctive therapy in chronic pain management. The cannabinoid system is likely to emerge as an important drug target in the future because of its apparent involvement in several therapeutically desirable effects.

Gamma-Hydroxybutyric Acid

Gamma-hydroxybutyric acid (GHB) is produced during the metabolism of GABA, but the function of this endogenous agent is unknown at present. The pharmacology of GHB is complex because there are two distinct binding sites. The protein that contains a high-affinity binding site (1 M) for GHB has recently been cloned, but its involvement in the cellular effects of GHB at pharmacologic concentrations remains unclear. The low-affinity binding site (1 mM) has been identified as the GABA_B receptor. In mice that lack GABA_B receptors, even very high doses of GHB have no effect; this suggests that GABA_B receptors are the sole mediators of GHB's pharmacologic action.

GHB was first synthesized in 1960 and introduced as a general anesthetic. Because of its narrow safety margin and its addictive potential, it is not available in the USA for this purpose at present. Before causing sedation and coma, GHB causes euphoria, enhanced sensory perceptions, a feeling of social closeness, and amnesia. These properties have made it a popular "club drug" that goes by colorful street names such as "liquid ecstasy," "grievous bodily harm," or "date rape drug." As the latter name suggests, GHB has been used in date rapes because it is odorless and can be readily dissolved in beverages. It is rapidly absorbed after ingestion and reaches a maximal plasma concentration 20–30 minutes after ingestion of a 10–20 mg/kg dose. The elimination half-life is about 30 minutes.

Although GABA_B receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than dopamine neurons. This is reflected by the EC₅₀s, which differ by about one order of magnitude and indicates the difference in coupling efficiency of the GABA_B receptor and the potassium channels responsible for the hyperpolarization. Because GHB is a weak agonist, only GABA neurons are inhibited at the concentrations typically obtained with recreational use. This feature may underlie the reinforcing effects of GHB and the basis for addiction to the drug. At higher doses, however, GHB also hyperpolarizes dopamine neurons, eventually completely inhibiting dopamine release. Such an inhibition of the VTA may in turn preclude its activation by other addictive drugs and may explain why GHB might have some usefulness as an "anticraving" compound.

LSD, Mescaline, & Psilocybin

The three drugs, LSD, mescaline, and psilocybin are commonly called hallucinogens because of their ability to alter consciousness such that the individual senses things that are not present. They induce, often in an unpredictable way, perceptual symptoms, including shape and color distortion. Psychosis-like manifestations (depersonalization, hallucinations, distorted time perception) have led some to classify these drugs as psychotomimetics. They also produce somatic symptoms (dizziness, nausea, paresthesias, and blurred vision). Some users have reported intense reexperiencing of perceptual effects (flashbacks) up to several years after the last drug exposure.

Hallucinogens differ from most other drugs described in this chapter in that they induce neither dependence nor addiction. However, repetitive exposure still leads to rapid tolerance (also called tachyphylaxis). Animals do not self-administer hallucinogens, suggesting that they are not rewarding to them. Additional studies show that these drugs also fail to stimulate dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive. Instead, hallucinogens increase glutamate release in the cortex, presumably by enhancing excitatory afferent input from the thalamus.

LSD is an ergot alkaloid. After synthesis, blotter paper or sugar cubes are sprinkled with the liquid and allowed to dry. When LSD is swallowed, psychoactive effects typically appear after 30 minutes and last 6–12 hours. During this time, subjects have impaired ability to make rational judgments and understand common dangers, which puts them at risk for accidents and personal injury.

In an adult, a typical dose is 20–30 mcg. LSD is considered neurotoxic and like most ergot alkaloids, may lead to strong contractions of the uterus that can induce abortion.

The main molecular target of LSD and other hallucinogens is the 5-HT_2A receptor. This receptor couples to G proteins of the G_q type and generates inositol trisphosphate (IP₃), leading to a release of intracellular calcium. Although hallucinogens, and LSD in particular, have been proposed for several therapeutic indications, efficacy has never been demonstrated.

Drugs that Mediate Their Effects Via Ionotropic Receptors

Nicotine

In terms of numbers affected, addiction to nicotine exceeds all other forms of addiction, touching more than 50% of all adults in some countries. Nicotine exposure occurs primarily through smoking of tobacco, which causes associated diseases that are responsible for many preventable deaths. The chronic use of chewing tobacco and snuff tobacco is also addictive.

Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine (see Chapter 6). Based on nicotine's enhancement of cognitive performance and the association of Alzheimer's dementia with a loss of ACh-releasing neurons from the nucleus basalis of Meynert, nAChRs are believed to play an important role in many cognitive processes. The rewarding effect of nicotine requires involvement of the VTA, in which nAChRs are expressed on dopamine neurons. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs. Recent work has identified ₄₂-containing channels in the VTA as the nAChRs that are required for the rewarding effects of nicotine. This statement is based on the observation that knockout mice deficient for the ₂ subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in vivo transfection of the ₂ subunit in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of ₇ subunits also contribute to the reinforcing effects of nicotine. These receptors are mainly expressed on synaptic terminals of excitatory afferents projecting onto the dopamine neurons. They also contribute to nicotine-evoked dopamine release and the long-term changes induced by the drugs related to addiction (eg, long-term synaptic potentiation of excitatory inputs).

Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and sleep problems. However, nicotine is among the most addictive drugs (relative risk = 4), and relapse after attempted cessation is very common.

Treatment

Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. Recently, two partial agonists of ₄₂-containing nAChRs have been characterized; the plant-extract cytisine and its synthetic derivative varenicline. Both work by occupying nAChRs on dopamine neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair the capacity to drive and has been associated with suicidal ideation. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behavioral therapies.

Many countries have banned smoking in public places to create smoke-free environments. This important step not only reduces passive smoking and the hazards of secondhand smoke, but also the risk that ex-smokers will be exposed to smoke, which as a contextual cue, may trigger relapse.

Benzodiazepines

Benzodiazepines are commonly prescribed as anxiolytics and sleep medications. They represent a moderate risk for abuse, which has to be weighed against their beneficial effects. Benzodiazepines are abused by some persons for their euphoriant effects, but most often abuse occurs concomitant with other drugs, eg, to attenuate anxiety during withdrawal from opioids.

Barbiturates, which preceded benzodiazepines as the most commonly abused sedative hypnotics (after ethanol), are now rarely prescribed to outpatients and therefore constitute a less common prescription drug problem than they did in the past. Street sales of barbiturates, however, continue. Management of barbiturate withdrawal and addiction is similar to that of benzodiazepines.

Although benzodiazepine dependence is very common, cases that fulfill all the diagnostic criteria for addiction are rare. Withdrawal from benzodiazepines occurs within days of stopping the medication and varies as a function of the half-life of elimination. Symptoms include irritability, insomnia, phono- and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks.

Benzodiazepines are positive modulators of the GABA_A receptor, increasing both single-channel conductance and open-channel probability. GABA_A receptors are pentameric structures consisting of , , and subunits (see Chapter 22). GABA receptors on dopamine neurons of the VTA lack ₁, a subunit that is typically present in GABA neurons. In addition, GABA_A receptors are expressed in much higher density on interneurons, so that a disinhibition of the mesolimbic dopamine system may explain the rewarding effects of benzodiazepines. Receptors containing ₅ subunits seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link ₂₃-containing receptors to alcohol dependence (the GABA_A receptor is also a target of alcohol, see following text). Taken together, a picture is emerging linking GABA_A receptors of specific subunit isoform composition to their therapeutic effects and to dependence and addiction induced with chronic exposure.

Alcohol

Alcohol (ethanol, see Chapter 23) is regularly used by a majority of the population in many Western countries. Although only a minority becomes dependent and addicted, abuse is a very serious public health problem because of the many diseases associated with alcoholism.

Pharmacology

The pharmacology of alcohol is complex, and no single receptor mediates all of its effects. On the contrary, alcohol alters the function of several receptors and cellular functions, including GABA_A receptors, Kir3/GIRK channels, adenosine reuptake (through the equilibrative nucleoside transporter, ENT1), glycine receptor, NMDA receptor, and 5-HT₃ receptor. They are all, with the exception of ENT1, either ionotropic receptors or ion channels. It is not clear which of these targets is responsible for the increase of dopamine release from the mesolimbic reward system. The inhibition of ENT1 is probably not responsible for the rewarding effects (ENT1 knockout mice drink more than controls) but seems to be involved in alcohol dependence through an accumulation of adenosine, stimulation of adenosine A2 receptors, and ensuing enhanced CREB signaling.

Dependence becomes apparent 6–12 hours after cessation of heavy drinking as a withdrawal syndrome that may include tremor (mainly of the hands), nausea and vomiting, excessive sweating, agitation, and anxiety. In some individuals, this is followed by visual, tactile, and auditory hallucinations 12–24 hours after cessation. Generalized seizures may manifest after 24–48 hours. Finally, 48–72 hours after cessation, an alcohol withdrawal delirium (delirium tremens) may become apparent in which the person hallucinates, is disoriented, and shows evidence of autonomic instability. Delirium tremens is associated with 5–15% mortality.

Treatment

Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longer-acting benzodiazepine such as chlordiazepoxide is preferred.

As in the treatment of all chronic drug abuse problems, heavy reliance is placed on psychosocial approaches to alcohol addiction. This is perhaps even more important for the alcoholic patient because of the ubiquitous presence of alcohol in many social contexts.

The pharmacologic treatment of alcohol addiction is limited, although several compounds, with different goals, have been used. Therapy is discussed in Chapter 23.

Ketamine & Phencyclidine (PCP)

Ketamine and PCP were developed as general anesthetics (see Chapter 25), but only ketamine is still used for this application. Both drugs, along with others, are now classified as "club drugs" and sold under names such as "angel dust," "Hog," and "Special K." They owe their effects to their use-dependent, noncompetitive antagonism of the NMDA receptor. The effects of these substances became apparent when patients undergoing surgery reported unpleasant vivid dreams and hallucinations after anesthesia. Ketamine and PCP are white crystalline powders in their pure forms, but on the street they are also sold as liquids, capsules, or pills, which can be snorted, ingested, injected, or smoked. Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, and visual alterations. At high doses, unpleasant out-of-body and near-death experiences have been reported. Although ketamine and phencyclidine do not cause dependence and addiction (relative risk = 1), chronic exposure, particularly to PCP, may lead to long-lasting psychosis closely resembling schizophrenia, which may persist beyond drug exposure.

Inhalants

Inhalant abuse is defined as recreational exposure to chemical vapors, such as nitrates, ketones, and aliphatic and aromatic hydrocarbons. These substances are present in a variety of household and industrial products that are inhaled by "sniffing," "huffing," or "bagging." Sniffing refers to inhalation from an open container, huffing to the soaking of a cloth in the volatile substance before inhalation, and bagging to breathing in and out of a paper or plastic bag filled with fumes. It is common for novices to start with sniffing and progress to huffing and bagging as addiction develops. Inhalant abuse is particularly prevalent in children and young adults.

The exact mechanism of action of most volatile substances remains unknown. Altered function of ionotropic receptors and ion channels throughout the central nervous system has been demonstrated for a few. Nitrous oxide, for example, binds to NMDA receptors and fuel additives enhance GABA_A receptor function. Most inhalants produce euphoria; increased excitability of the VTA has been documented for toluene and may underlie its addiction risk. Other substances, such as amyl nitrite ("poppers"), primarily produce smooth muscle relaxation and enhance erection, but are not addictive. With chronic exposure to the aromatic hydrocarbons (eg, benzene, toluene), toxic effects can be observed in many organs, including white matter lesions in the central nervous system. Management of overdose remains supportive.

Drugs That Bind to Transporters of Biogenic Amines

Cocaine

The prevalence of cocaine abuse has increased greatly over the last decade and now represents a major public health problem worldwide. Cocaine is highly addictive (relative risk = 5), and its use is associated with a number of complications.

Cocaine is an alkaloid found in the leaves of Erythroxylon coca, a shrub indigenous to the Andes. For more than 100 years, it has been extracted and used in clinical medicine, mainly as a local anesthetic and to dilate pupils in ophthalmology. Sigmund Freud famously proposed its use to treat depression and alcohol dependence, but addiction quickly brought an end to this idea.

Cocaine hydrochloride is a water-soluble salt that can be injected or absorbed by any mucosal membrane (eg, nasal snorting). When heated in an alkaline solution, it is transformed into the free base, "crack cocaine," which can then be smoked. Inhaled crack cocaine is rapidly absorbed in the lungs and penetrates swiftly into the brain, producing an almost instantaneous "rush."

In the peripheral nervous system, cocaine inhibits voltage-gated sodium channels, thus blocking initiation and conduction of action potentials (see Chapter 26). This effect, however, seems responsible for neither the acute rewarding nor the addictive effects. In the central nervous system, cocaine blocks the uptake of dopamine, noradrenaline, and serotonin through their respective transporters. The block of the dopamine transporter (DAT), by increasing dopamine concentrations in the nucleus accumbens, has been implicated in the rewarding effects of cocaine (Figures 32–4 and 32–5). In fact, the rewarding effects of cocaine are abolished in mice with a cocaine-insensitive DAT. The activation of the sympathetic nervous system results mainly from blockage of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Users typically lose their appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures. Cocaine overdose may lead to hyperthermia, coma, and death.

Susceptible individuals may become dependent and addicted after only a few exposures to cocaine. Although a withdrawal syndrome is reported, it is not as strong as that observed with opioids. Tolerance may develop, but in some users a reverse tolerance is observed; that is, they become sensitized to small doses of cocaine. This behavioral sensitization is in part context-dependent. Cravings are very strong and underline the very high addiction liability of cocaine. To date, no specific antagonist is available, and the management of intoxication remains supportive. Developing a pharmacologic treatment for cocaine addiction is a top priority.

Amphetamines

Amphetamines are a group of synthetic, indirect-acting sympathomimetic drugs that cause the release of endogenous biogenic amines, such as dopamine and noradrenaline (see Chapters 6 and 9). Amphetamine, methamphetamine, and their many derivatives exert their effects by reversing the action of biogenic amine transporters at the plasma membrane. Amphetamines are substrates of these transporters and are taken up into the cell (Figure 32–5). Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT; see Figure 6-4), depleting synaptic vesicles of their neurotransmitter content. As a consequence, levels of dopamine (or other transmitter amine) in the cytoplasm increase and quickly become sufficient to cause release into the synapse by reversal of the plasma membrane DAT. Normal vesicular release of dopamine consequently decreases (because synaptic vesicles contain less transmitter), whereas nonvesicular release increases. Similar mechanisms apply for other biogenic amines (serotonin and norepinephrine).

Together with GHB and ecstasy, amphetamines are often referred to as "club drugs," because they are increasingly popular in the club scene. They are often produced in small clandestine laboratories, which makes their precise chemical identification difficult. They differ from ecstasy chiefly in the context of use: intravenous administration and "hard core" addiction is far more common with amphetamines, especially methamphetamine. In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dopamine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines.

Unlike many other abused drugs, amphetamines are neurotoxic. The exact mechanism is not known, but neurotoxicity depends on the NMDA receptor and affects mainly serotonin and dopamine neurons.

Amphetamines are typically taken initially in pill form by abusers, but can also be smoked or injected. Heavy users often progress rapidly to intravenous administration. Within hours after oral ingestion, amphetamines increase alertness, cause euphoria, agitation, and confusion. Bruxism (tooth grinding) and skin flushing may occur. Effects on heart rate may be minimal with some compounds (eg, methamphetamine), but with increasing dosage these agents often lead to tachycardia and dysrhythmias. Hypertensive crisis and vasoconstriction may lead to stroke. Spread of HIV and hepatitis infection in inner cities has been closely associated with needle sharing by intravenous users of methamphetamine.

With chronic use, amphetamine tolerance may develop, leading to dose escalation. Withdrawal consists of dysphoria, drowsiness (in some cases, insomnia), and general irritability.

Ecstasy (MDMA)

Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylene-dioxymethamphetamine (MDMA). MDMA was originally used in some forms of psychotherapy but no medically useful effects were documented. This is perhaps not surprising, because the main effect of ecstasy appears to be to foster feelings of intimacy and empathy without impairing intellectual capacities. Today, MDMA and its many derivatives are often produced in small quantities in ad hoc laboratories and distributed at parties or "raves," where it is taken orally. Ecstasy therefore is the prototypical designer drug and, as such, is increasingly popular.

Similar to the amphetamines, MDMA causes release of biogenic amines by reversing the action of their respective transporters. It has a preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the extracellular concentration of serotonin. This release is so profound that there is a marked intracellular depletion for 24 hours after a single dose. With repetitive administration, serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impairment in heavy users of MDMA.

In contrast, there is a wide consensus that MDMA has several acute toxic effects, in particular hyperthermia, which along with dehydration (eg, caused by an all-night dance party) may be fatal. Other complications include serotonin syndrome (mental status change, autonomic hyperactivity, and neuromuscular abnormalities, see Chapter 16) and seizures. Following warnings about the dangers of MDMA, some users have attempted to compensate for hyperthermia by drinking excessive amounts of water, causing water intoxication involving severe hyponatremia, seizures, and even death.

Withdrawal is marked by a mood "offset" characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.

Taken together, the evidence for irreversible damage to the brain, although not completely convincing, implies that even occasional recreational use of MDMA cannot be considered safe.

Clinical Pharmacology of Dependence & Addiction

To date no single pharmacologic treatment (even in combination with behavioral interventions) efficiently eliminates addiction. This is not to say that addiction is irreversible. Pharmacologic interventions may in fact be useful at all stages of the disease. This is particularly true in the case of a massive overdose, in which reversal of drug action may be a life-saving measure. However, in this regard, FDA-approved antagonists are available only for opioids and benzodiazepines.

Pharmacologic interventions may also aim to alleviate the withdrawal syndrome, particularly after opioid exposure. On the assumption that withdrawal reflects at least in part a hyperactivity of central adrenergic systems, the ₂-adrenoceptor agonist clonidine (also used as a centrally active antihypertensive drug, see Chapter 11) has been used with some success to attenuate withdrawal. Today, most clinicians prefer to manage opioid withdrawal by very slowly tapering the administration of long-acting opioids.

Another widely accepted treatment is substitution of a legally available agonist that acts at the same receptor as the abused drug. This approach has been approved for opioids and nicotine. For example, heroin addicts may receive methadone to replace heroin; smoking addicts may receive nicotine continuously via a transdermal patch system to replace smoking. In general, a rapid-acting substance is replaced with one that acts or is absorbed more slowly. Substitution treatments are largely justified by the benefits of reducing associated health risks, the reduction of drug-associated crime, and better social integration. Although dependence persists, it may be possible, with the support of behavioral interventions, to motivate drug users to gradually reduce the dose and become abstinent.

The biggest challenge is the treatment of addiction itself. Several approaches have been proposed, but all remain experimental. One approach is to pharmacologically reduce cravings. The -opioid receptor antagonist and partial agonist naltrexone is FDA-approved for this indication in opioid and alcohol addiction. Its effect is modest and may involve a modulation of endogenous opioid systems.

Clinical trials are currently being conducted with a number of drugs, including the high-affinity GABA_B-receptor agonist baclofen, and initial results have shown a significant reduction of craving. This effect may be mediated by the inhibition of the dopamine neurons of the VTA, which is possible at baclofen concentrations obtained by oral administration because of its very high affinity for the GABA_B receptor.

Rimonabant is an inverse agonist of the CB₁ receptor, initially developed for smoking cessation and to facilitate weight loss. The drug is currently approved in Europe and the USA for use in conjunction with diet and exercise for patients with a body mass index above 30 kg/m² (27 kg/m² if associated risk factors, such as type 2 diabetes or dyslipidemia are present). Although a recent large-scale study confirmed that rimonabant is effective for smoking cessation and the prevention of weight gain in smokers who quit, this indication has not been approved. In fact, because of frequent adverse effects—most notably severe depression carrying a substantial risk of suicide—the future of rimonabant remains unclear. Although the cellular mechanism of rimonabant remains to be elucidated, data in rodents convincingly demonstrate that this compound can reduce self-administration in naive as well as drug-experienced animals.

Summary: Drugs Used to Treat Dependence and Addiction

References

General

Pharmacology of Drugs of Abuse