32. Drugs of Abuse ¾ Christian Luscher,
MD
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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 compulsive¾the hallmark of addiction.
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I. 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 dependence, while "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 abuse¾it 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 Box: Animal Models in Addiction Research). While dependence will invariably occur with chronic exposure, only a fraction of subjects will develop a habit, lose control, and become addicted. For example, very few patients who receive opioids as analgesics will desire the drug after withdrawal. And only one person out of six will become 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.
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ANIMAL MODELS IN ADDICTION RESEARCH
Many of the recent advances in addiction research have been made possible by the use of animal models. Since drugs of abuse are not only rewarding but also reinforcing, an animal will learn a behavior (eg, press a lever) when paired with drug administration. In such a self-administration paradigm, the number of times an animal is willing to press the lever in order to obtain a single dose reflects the strength of reinforcement and is therefore a measure of the rewarding properties of a drug. Observing withdrawal signs specific for rodents (eg, escape jumps or "wet-dog" shakes after abrupt termination of chronic morphine administration) allows the quantification of dependence. Behavioral tests for addiction in the rodent have proven difficult to develop and so far no test fully captures the complexity of the disease. However it is possible to model core components of addiction by monitoring behavioral sensitization and conditioned place preference. In the first test, an increase in locomotor activity is observed with intermittent drug exposure. The latter tests for the preference of a particular environment associated with drug exposure by measuring the time an animal spends in the compartment where a drug was received compared with the compartment where only saline was injected (conditioned place preference). Both tests have in common that they are sensitive to cue-conditioned effects of addictive drugs. Recent findings suggest that prolonged self-administration of cocaine leads to behaviors in rats that closely resemble human addiction. Such "addicted rats" are very strongly motivated to seek cocaine, continue looking for the drug even when no longer available, and self-administer cocaine in spite of negative consequences, such as an electric foot shock. These findings suggest that addiction is a disease that does not respect species boundaries.
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ADDICTIVE DRUGS INCREASE THE LEVEL OF DOPAMINE: REINFORCEMENT
In order 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 brainstem, which projects to the nucleus accumbens, the amygdala, 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 Box: 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 Gio-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets monoamine transporters (Table 32-1). G protein-coupled receptors (GPCRs) that are of the Gio family inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. In the VTA, the action of these drugs is preferentially on the g-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 of or stimulate nonvesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures. While 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.
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THE DOPAMINE HYPOTHESIS OF ADDICTION
In the earliest version of the hypothesis described in this chapter, mesolimbic dopamine was believed to be the neurochemical correlate of pleasure and reward. However, during the past decade, experimental evidence has led to several revisions. Phasic dopamine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneering observations in monkeys that dopamine neurons in the VTA are most efficiently activated by a reward (eg, a few drops of fruit juice) that is not anticipated. When the animal learns to predict the occurrence of a reward (eg, by pairing it with a stimulus such as a sound), dopamine neurons stop responding to the reward itself (juice), but increase their firing rate when the conditioned stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons are inhibited below their baseline activity and become completely silent. In other words, the mesolimbic system continuously scans the reward situation. It increases its activity when reward is larger than expected, and shuts down in the opposite case, thus coding for the prediction error of reward.
Under physiologic conditions the mesolimbic dopamine signal could represent a learning signal responsible for reinforcing constructive behavioral adaptation (eg, learning to press a lever for food). Addictive drugs, by directly increasing dopamine, would generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforcement, further drug consumption, and addiction.
This appealing hypothesis has been challenged based on the observation that some reward and drug-related learning is still possible in the absence of dopamine. Another intriguing observation is that mice genetically modified to lack the primary molecular target of cocaine, the dopamine transporter DAT, still self-administer the drug. Only when transporters of other biogenic amines are also knocked out does cocaine completely lose its rewarding properties. However, in DAT-/- mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive amine transporters are able to clear some dopamine. When cocaine is given, these transporters (NET, SERT) are also inhibited and dopamine is again increased. This concept is supported by newer evidence showing that deletion of the cocaine binding site on DAT leaves basal dopamine levels unchanged but abolishes the rewarding effect of cocaine.
The dopamine hypothesis of addiction has also been challenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore negative reinforcers) also activate the VTA. However, the neurons in the VTA that are activated by aversive stimuli do not release dopamine, and dopamine neurons are actually inhibited by aversive stimuli. These findings suggest that the controversy can be resolved in favor of dopamine reward theories.
Whatever the precise role of dopamine under physiologic conditions, all addictive drugs strongly increase its concentration in target structures of the mesolimbic projection. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction.
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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-effects¾eg, respiratory depression¾that 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 u opioid receptor function (pharmacodynamic tolerance). In fact, many u opioid receptor agonists promote strong receptor phosphorylation that triggers the recruitment of the adaptor protein b-arrestin, causing G proteins to uncouple from the receptor and to internalize within minutes. Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit b-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 following chronic exposure to most drugs of abuse. Withdrawal from opioids in humans is particularly strong and is described below. Studies in rodents have added significantly to our understanding of the neural and molecular mechanisms that underlie dependence. For example, dependence, as well as analgesia and reward, are abolished in knockout mice lacking the u opioid receptor, but not in mice lacking other opioid receptors (d, k). While activation of the u opioid receptor initially strongly inhibits adenylyl cyclase, this inhibition becomes weaker after several days of repeated exposure. The waning 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 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 k 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 32-2). These cells express k 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 are at high risk of relapsing. Relapse is typically triggered by one of the following three conditions: reexposure to the drug of abuse, 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). For example, cravings may recur at the presentation of contextual cues (eg, people, places, or drug paraphernalia), suggesting the involvement of learning and memory systems. If dopamine release codes for the prediction error of reward (see Box: The Dopamine Hypothesis of Addiction), the 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. Current research therefore focuses on the effects of drugs on associative forms of synaptic plasticity, such as long-term potentiation (LTP), that underlie learning and memory (see Box: Synaptic Plasticity & Addiction).
Large individual differences exist in vulnerability to 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 fraction of dependent users will go on to become addicted. 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. While 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.
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SYNAPTIC PLASTICITY & ADDICTION
Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N-methyl-D-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (postsynaptic activity). Correlated pre- and postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. Because associativity is a critical component, LTP has become a leading candidate mechanism underlying learning and memory. LTP can be elicited at glutamatergic synapses of the mesolimbic reward system and is modulated by dopamine. Drugs of abuse could therefore interfere with LTP at sites of convergence of dopamine and glutamate projections (eg, nucleus accumbens or prefrontal cortex). Interestingly, exposure to an addictive drug triggers LTP at excitatory afferents and reduces GABAA receptor-mediated inhibition of the VTA, thus increasing the excitability of dopamine neurons. Genetic manipulations in mice that abolish LTP at this synapse also have effects on behavioral paradigms that model core components of addiction such as conditioned place preference, further supporting the idea that LTP is involved in context-dependent components of relapse. Similarly, interfering with transcriptional signaling implicated in the late phases of LTP affects conditioned place preference.
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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). These agents primarily target cortical and thalamic circuits unlike addictive drugs, which primarily target the mesolimbic dopamine system (see above). Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A 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 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 consumption. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.
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II. BASIC PHARMACOLOGY OF DRUGS OF ABUSE
INTRODUCTION
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). The first group contains the opioids, cannabinoids, g-hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through Gio 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 GIO-COUPLED RECEPTORS
OPIOIDS
Pharmacology & Clinical Aspects
As described in Chapter 31, the opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the u, k, and d 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, u opioid receptors are selectively expressed on GABA neurons (which they inhibit), while k opioid receptors are expressed on and inhibit dopamine neurons. This may explain why u opioid agonists cause euphoria while k agonists induce dysphoria (see also Figure 32-3). In line with these observations, the rewarding effects of morphine are absent in knockout mice lacking u receptors but persist when either of the other opioid receptors are ablated. In the VTA, u opioids cause an inhibition of GABAergic inhibitory interneurons that leads eventually to a disinhibition of dopamine neurons
The most commonly abused u 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 will 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 widely used scale
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) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. The much longer half-life of methadone 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 (Figure 32-3). 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, comprise several pharmacologically active substances including D9-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. 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 D9-THC analog dronabinol is the only Food and Drug Administration-approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial D9-THC analog, may be reintroduced in the USA in the near future. 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 (GHB)
Gamma-hydroxybutyric acid is produced endogenously 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 uM) 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 GABAB receptor (Figure 32-3). In mice that lack GABAB receptors even very high doses of GHB have no effect, suggesting that GABAB receptors are the sole mediators of GHB's pharmacologic action.
Gamma-hydroxybutyric acid 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 following ingestion of a 10-20 mg/kg dose. The elimination half-life is about 30 minutes.
Although GABAB receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than dopamine neurons (the EC50 differs by about one order of magnitude). 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 utility as an "anticraving" compound.
LSD, MESCALINE, & PSILOCYBIN
These three drugs 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 will not self-administer hallucinogens, suggesting that they are not rewarding. 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.
The molecular target of hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the Gq 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
Pharmacology
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 addicting.
Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine. 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, where 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 a4b2-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 b2 subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in-vivo transfection of the b2 subunit in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of a7 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 sleeplessness. However, nicotine is among the most addictive drugs (relative risk = 4, ), and relapse after attempted cessation is very common.
Treatment
Treatment for nicotine addiction includes substituting nicotine that is chewed, inhaled, or transdermally delivered for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. At present, all available agents seem to be similarly effective in relieving craving, controlling the habit, and facilitating quitting. In addition, the antidepressant bupropion has been 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.
While 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 GABAA receptor, increasing both single channel conductance and open-channel probability. GABAA receptors are pentameric structures consisting of a, b, and g subunits. GABA receptors on dopamine neurons of the VTA lack a1, a subunit that is typically present in GABA neurons. In addition, GABAA 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 a5 seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link a2g3-containing receptors to alcohol dependence (the GABAA receptor is also a target of alcohol, see below). Taken together, a picture is emerging linking GABAA receptors of specific subunit composition to their therapeutic effects and to dependence and addiction induced with chronic exposure.
ALCOHOL
Introduction
Alcohol 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 GABAA 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 cases where 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. Disulfiram has been used as an adjunct to create aversion to drinking. Disulfiram inhibits acetaldehyde dehydrogenase, causing nausea, vomiting, and dysphoria with coincident alcohol use. Recently the efficacy of disulfiram has been questioned, and no large trials are available that conclusively demonstrate increased abstinence.
Naltrexone is an antagonist and partial agonist of the u opioid receptor, which may decrease the craving for alcohol, resulting in fewer relapses. Although most, but not all, studies found that naltrexone decreases relapses, the effect is modest. Combining naltrexone therapy with cognitive behavioral therapy may enhance benefit.
The antiepileptic compound topiramate facilitates GABA function and antagonizes glutamate receptors (presumably the AMPA type), and may decrease mesocorticolimbic dopamine release after alcohol and reduce cravings. However, topiramate does not have FDA approval for this indication.
In Europe several trials have been carried out with acamprosate, an NMDA receptor antagonist. However, most patients returned to drinking while still using the drug. A direct comparison with naltrexone showed acamprosate to be less effective.
KETAMINE & PHENCYCLIDINE (PCP)
Ketamine and PCP were developed as general anesthetics, 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 a 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 GABAA 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 past decade and now represents a major public health problem worldwide. Cocaine is highly addictive (relative risk = 5, Table 32-1), 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 (Figure 32-4). In fact, rewarding effects of cocaine are abolished in mice with a cocaine-insensitive DAT. The activation of the sympathetic nervous system results mainly from the block of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Subjects typically lose appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and generalized or partial 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 the one 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 32-4). Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT), 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), while 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, while 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, 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 methylenedioxymethamphetamine (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, 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.
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III. 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 only available 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 a2-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 tapering very slowly 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 rapidly 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. While 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 taken, but all remain experimental. One approach is to pharmacologically reduce cravings. The u 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 GABAB-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 GABAB receptor.
Rimonabant is a novel cannabinoid antagonist that should soon become available for the treatment of addiction. Initially developed for nicotine addiction, it may be useful in the treatment of abuse of cocaine, heroin, and alcohol. Although its cellular mechanism is unclear, data in rodents convincingly demonstrate that this compound can reduce self-administration in naive as well as in drug-experienced animals.
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 compulsive¾the hallmark of addiction.
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 dependence, while "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 abuse¾it 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 Box: Animal Models in Addiction Research). While dependence will invariably occur with chronic exposure, only a fraction of subjects will develop a habit, lose control, and become addicted. For example, very few patients who receive opioids as analgesics will desire the drug after withdrawal. And only one person out of six will become 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.
ANIMAL MODELS IN ADDICTION RESEARCH
Many of the recent advances in addiction research have been made possible by the use of animal models. Since drugs of abuse are not only rewarding but also reinforcing, an animal will learn a behavior (eg, press a lever) when paired with drug administration. In such a self-administration paradigm, the number of times an animal is willing to press the lever in order to obtain a single dose reflects the strength of reinforcement and is therefore a measure of the rewarding properties of a drug. Observing withdrawal signs specific for rodents (eg, escape jumps or "wet-dog" shakes after abrupt termination of chronic morphine administration) allows the quantification of dependence. Behavioral tests for addiction in the rodent have proven difficult to develop and so far no test fully captures the complexity of the disease. However it is possible to model core components of addiction by monitoring behavioral sensitization and conditioned place preference. In the first test, an increase in locomotor activity is observed with intermittent drug exposure. The latter tests for the preference of a particular environment associated with drug exposure by measuring the time an animal spends in the compartment where a drug was received compared with the compartment where only saline was injected (conditioned place preference). Both tests have in common that they are sensitive to cue-conditioned effects of addictive drugs. Recent findings suggest that prolonged self-administration of cocaine leads to behaviors in rats that closely resemble human addiction. Such "addicted rats" are very strongly motivated to seek cocaine, continue looking for the drug even when no longer available, and self-administer cocaine in spite of negative consequences, such as an electric foot shock. These findings suggest that addiction is a disease that does not respect species boundaries.
ADDICTIVE DRUGS INCREASE THE LEVEL OF DOPAMINE: REINFORCEMENT
In order 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 brainstem, which projects to the nucleus accumbens, the amygdala, 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 Box: 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 Gio-coupled receptors, a second group interacts with ionotropic receptors or ion channels, and a third group targets monoamine transporters (Table 32-1). G protein-coupled receptors (GPCRs) that are of the Gio family inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. In the VTA, the action of these drugs is preferentially on the g-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 of or stimulate nonvesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures. While 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.
THE DOPAMINE HYPOTHESIS OF ADDICTION
In the earliest version of the hypothesis described in this chapter, mesolimbic dopamine was believed to be the neurochemical correlate of pleasure and reward. However, during the past decade, experimental evidence has led to several revisions. Phasic dopamine release may actually code for the prediction error of reward rather than the reward itself. This distinction is based on pioneering observations in monkeys that dopamine neurons in the VTA are most efficiently activated by a reward (eg, a few drops of fruit juice) that is not anticipated. When the animal learns to predict the occurrence of a reward (eg, by pairing it with a stimulus such as a sound), dopamine neurons stop responding to the reward itself (juice), but increase their firing rate when the conditioned stimulus (sound) occurs. Finally, if reward is predicted but not delivered (sound but no juice), dopamine neurons are inhibited below their baseline activity and become completely silent. In other words, the mesolimbic system continuously scans the reward situation. It increases its activity when reward is larger than expected, and shuts down in the opposite case, thus coding for the prediction error of reward.
Under physiologic conditions the mesolimbic dopamine signal could represent a learning signal responsible for reinforcing constructive behavioral adaptation (eg, learning to press a lever for food). Addictive drugs, by directly increasing dopamine, would generate a strong but inappropriate learning signal, thus hijacking the reward system and leading to pathologic reinforcement, further drug consumption, and addiction.
This appealing hypothesis has been challenged based on the observation that some reward and drug-related learning is still possible in the absence of dopamine. Another intriguing observation is that mice genetically modified to lack the primary molecular target of cocaine, the dopamine transporter DAT, still self-administer the drug. Only when transporters of other biogenic amines are also knocked out does cocaine completely lose its rewarding properties. However, in DAT-/- mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive amine transporters are able to clear some dopamine. When cocaine is given, these transporters (NET, SERT) are also inhibited and dopamine is again increased. This concept is supported by newer evidence showing that deletion of the cocaine binding site on DAT leaves basal dopamine levels unchanged but abolishes the rewarding effect of cocaine.
The dopamine hypothesis of addiction has also been challenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore negative reinforcers) also activate the VTA. However, the neurons in the VTA that are activated by aversive stimuli do not release dopamine, and dopamine neurons are actually inhibited by aversive stimuli. These findings suggest that the controversy can be resolved in favor of dopamine reward theories.
Whatever the precise role of dopamine under physiologic conditions, all addictive drugs strongly increase its concentration in target structures of the mesolimbic projection. This suggests that high levels of dopamine may actually be at the origin of the adaptive changes that underlie dependence and addiction.
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-effects¾eg, respiratory depression¾that 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 u opioid receptor function (pharmacodynamic tolerance). In fact, many u opioid receptor agonists promote strong receptor phosphorylation that triggers the recruitment of the adaptor protein b-arrestin, causing G proteins to uncouple from the receptor and to internalize within minutes. Since this decreases signaling, it is tempting to explain tolerance by such a mechanism. However, morphine, which strongly induces tolerance, does not recruit b-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 following chronic exposure to most drugs of abuse. Withdrawal from opioids in humans is particularly strong and is described below. Studies in rodents have added significantly to our understanding of the neural and molecular mechanisms that underlie dependence. For example, dependence, as well as analgesia and reward, are abolished in knockout mice lacking the u opioid receptor, but not in mice lacking other opioid receptors (d, k). While activation of the u opioid receptor initially strongly inhibits adenylyl cyclase, this inhibition becomes weaker after several days of repeated exposure. The waning 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 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 k 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 32-2). These cells express k 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 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 are at high risk of relapsing. Relapse is typically triggered by one of the following three conditions: reexposure to the drug of abuse, 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). For example, cravings may recur at the presentation of contextual cues (eg, people, places, or drug paraphernalia), suggesting the involvement of learning and memory systems. If dopamine release codes for the prediction error of reward (see Box: The Dopamine Hypothesis of Addiction), the 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. Current research therefore focuses on the effects of drugs on associative forms of synaptic plasticity, such as long-term potentiation (LTP), that underlie learning and memory (see Box: Synaptic Plasticity & Addiction).
Large individual differences exist in vulnerability to 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 fraction of dependent users will go on to become addicted. 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. While 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.
SYNAPTIC PLASTICITY & ADDICTION
Long-term potentiation (LTP) is a form of experience-dependent synaptic plasticity that is induced by activating glutamate receptors of the N-methyl-D-aspartate (NMDA) type. Since NMDA receptors are blocked by magnesium at negative potentials, their activation requires the concomitant release of glutamate (presynaptic activity) onto a receiving neuron that is depolarized (postsynaptic activity). Correlated pre- and postsynaptic activity durably enhances synaptic efficacy and triggers the formation of new connections. Because associativity is a critical component, LTP has become a leading candidate mechanism underlying learning and memory. LTP can be elicited at glutamatergic synapses of the mesolimbic reward system and is modulated by dopamine. Drugs of abuse could therefore interfere with LTP at sites of convergence of dopamine and glutamate projections (eg, nucleus accumbens or prefrontal cortex). Interestingly, exposure to an addictive drug triggers LTP at excitatory afferents and reduces GABAA receptor-mediated inhibition of the VTA, thus increasing the excitability of dopamine neurons. Genetic manipulations in mice that abolish LTP at this synapse also have effects on behavioral paradigms that model core components of addiction such as conditioned place preference, further supporting the idea that LTP is involved in context-dependent components of relapse. Similarly, interfering with transcriptional signaling implicated in the late phases of LTP affects conditioned place preference.
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). These agents primarily target cortical and thalamic circuits unlike addictive drugs, which primarily target the mesolimbic dopamine system (see above). Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A 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 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 consumption. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.
INTRODUCTION
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). The first group contains the opioids, cannabinoids, g-hydroxybutyric acid (GHB), and the hallucinogens, which all exert their action through Gio 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 GIO-COUPLED RECEPTORS
OPIOIDS
Pharmacology & Clinical Aspects
As described in Chapter 31, the opioids comprise a large family of endogenous and exogenous agonists at three G protein-coupled receptors: the u, k, and d 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, u opioid receptors are selectively expressed on GABA neurons (which they inhibit), while k opioid receptors are expressed on and inhibit dopamine neurons. This may explain why u opioid agonists cause euphoria while k agonists induce dysphoria (see also Figure 32-3). In line with these observations, the rewarding effects of morphine are absent in knockout mice lacking u receptors but persist when either of the other opioid receptors are ablated. In the VTA, u opioids cause an inhibition of GABAergic inhibitory interneurons that leads eventually to a disinhibition of dopamine neurons
The most commonly abused u 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 will 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 widely used scale
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) is often substituted for the shorter-acting, more rewarding, opioid (eg, heroin). For substitution therapy, methadone is given orally once daily, facilitating supervised intake. The much longer half-life of methadone 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 (Figure 32-3). 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, comprise several pharmacologically active substances including D9-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. 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 D9-THC analog dronabinol is the only Food and Drug Administration-approved cannabinoid agonist currently marketed in the USA and some European countries. Nabilone, an older commercial D9-THC analog, may be reintroduced in the USA in the near future. 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 (GHB)
Gamma-hydroxybutyric acid is produced endogenously 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 uM) 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 GABAB receptor (Figure 32-3). In mice that lack GABAB receptors even very high doses of GHB have no effect, suggesting that GABAB receptors are the sole mediators of GHB's pharmacologic action.
Gamma-hydroxybutyric acid 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 following ingestion of a 10-20 mg/kg dose. The elimination half-life is about 30 minutes.
Although GABAB receptors are expressed on all neurons of the VTA, GABA neurons are much more sensitive to GHB than dopamine neurons (the EC50 differs by about one order of magnitude). 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 utility as an "anticraving" compound.
LSD, MESCALINE, & PSILOCYBIN
These three drugs 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 will not self-administer hallucinogens, suggesting that they are not rewarding. 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.
The molecular target of hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the Gq 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
Pharmacology
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 addicting.
Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine. 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, where 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 a4b2-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 b2 subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in-vivo transfection of the b2 subunit in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of a7 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 sleeplessness. However, nicotine is among the most addictive drugs (relative risk = 4, ), and relapse after attempted cessation is very common.
Treatment
Treatment for nicotine addiction includes substituting nicotine that is chewed, inhaled, or transdermally delivered for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. At present, all available agents seem to be similarly effective in relieving craving, controlling the habit, and facilitating quitting. In addition, the antidepressant bupropion has been 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.
While 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 GABAA receptor, increasing both single channel conductance and open-channel probability. GABAA receptors are pentameric structures consisting of a, b, and g subunits. GABA receptors on dopamine neurons of the VTA lack a1, a subunit that is typically present in GABA neurons. In addition, GABAA 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 a5 seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link a2g3-containing receptors to alcohol dependence (the GABAA receptor is also a target of alcohol, see below). Taken together, a picture is emerging linking GABAA receptors of specific subunit composition to their therapeutic effects and to dependence and addiction induced with chronic exposure.
ALCOHOL
Introduction
Alcohol 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 GABAA 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 cases where 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. Disulfiram has been used as an adjunct to create aversion to drinking. Disulfiram inhibits acetaldehyde dehydrogenase, causing nausea, vomiting, and dysphoria with coincident alcohol use. Recently the efficacy of disulfiram has been questioned, and no large trials are available that conclusively demonstrate increased abstinence.
Naltrexone is an antagonist and partial agonist of the u opioid receptor, which may decrease the craving for alcohol, resulting in fewer relapses. Although most, but not all, studies found that naltrexone decreases relapses, the effect is modest. Combining naltrexone therapy with cognitive behavioral therapy may enhance benefit.
The antiepileptic compound topiramate facilitates GABA function and antagonizes glutamate receptors (presumably the AMPA type), and may decrease mesocorticolimbic dopamine release after alcohol and reduce cravings. However, topiramate does not have FDA approval for this indication.
In Europe several trials have been carried out with acamprosate, an NMDA receptor antagonist. However, most patients returned to drinking while still using the drug. A direct comparison with naltrexone showed acamprosate to be less effective.
KETAMINE & PHENCYCLIDINE (PCP)
Ketamine and PCP were developed as general anesthetics, 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 a 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 GABAA 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 past decade and now represents a major public health problem worldwide. Cocaine is highly addictive (relative risk = 5, Table 32-1), 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 (Figure 32-4). In fact, rewarding effects of cocaine are abolished in mice with a cocaine-insensitive DAT. The activation of the sympathetic nervous system results mainly from the block of the norepinephrine transporter (NET) and leads to an acute increase in arterial pressure, tachycardia, and often, ventricular arrhythmias. Subjects typically lose appetite, are hyperactive, and sleep little. Cocaine exposure increases the risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and generalized or partial 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 the one 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 32-4). Once in the cell, amphetamines interfere with the vesicular monoamine transporter (VMAT), 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), while 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, while 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, 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 methylenedioxymethamphetamine (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, 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.
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 only available 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 a2-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 tapering very slowly 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 rapidly 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. While 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 taken, but all remain experimental. One approach is to pharmacologically reduce cravings. The u 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 GABAB-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 GABAB receptor.
Rimonabant is a novel cannabinoid antagonist that should soon become available for the treatment of addiction. Initially developed for nicotine addiction, it may be useful in the treatment of abuse of cocaine, heroin, and alcohol. Although its cellular mechanism is unclear, data in rodents convincingly demonstrate that this compound can reduce self-administration in naive as well as in drug-experienced animals.
