DRUGS THAT MEDIATE THEIR EFFECTS VIA IONOTROPIC RECEPTORS
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 chew-ing tobacco and snuff tobacco is also addictive.
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, in which nAChRs are expressed on dopamine neurons.
When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs. Recent work has identi-fied α4β2-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 β2 subunit lose interest in self-administering nicotine, and that in these mice, this behavior can be restored through an in vivo trans-fection of the β2 subunit in neurons of the VTA. Electrophysiologic evidence suggests that homomeric nAChRs made exclusively of α7 subunits also contribute to the reinforcing effects of nicotine. These receptors are mainly expressed on synaptic terminals of excit-atory afferents projecting onto the dopamine neurons. They also contribute to nicotine-evoked dopamine release and the long-term changes induced by the drugs related to addiction (eg, long-term synaptic potentiation of excitatory inputs).Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and sleep problems. However, nicotine is among the most addictive drugs (relative risk 4), and relapse after attempted cessation is very common.
Treatments for nicotine addiction include nicotine itself in forms that are slowly absorbed and several other drugs. Nicotine that is chewed, inhaled, or transdermally delivered can be substituted for the nicotine in cigarettes, thus slowing the pharmacokinetics and eliminating the many complications associated with the toxic substances found in tobacco smoke. Recently, two partial agonists of α4β2-containing nAChRs have been characterized; the plant-extract cytisine and its synthetic derivative varenicline. Both work by occupying nAChRs on dopamine neurons of the VTA, thus preventing nicotine from exerting its action. Varenicline may impair the capacity to drive and has been associated with suicidal ideation. The antidepressant bupropion is approved for nicotine cessation therapy. It is most effective when combined with behav-ioral 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 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 mostcommonly 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.
Benzodiazepine dependence is very common, and diagnosis of addiction probably often missed. Withdrawal from benzodiaz-epines occurs within days of stopping the medication and varies as a function of the half-life of elimination. Symptoms include irri-tability, insomnia, phonophobia and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks.
Benzodiazepines are positive modulators of the GABAA recep-tor, increasing both single-channel conductance and open-channel probability. GABAA receptors are pentameric structures consisting of α, β, and γ subunits . GABA receptors on dopamine neurons of the VTA lack α1, a subunit isoform that is present in GABA neurons nearby (ie, interneurons). Because of this difference, unitary synaptic currents in interneurons are larger than those in dopamine neurons, and when this difference is amplified by benzodiazepines, interneurons fall silent. GABA is no longer released, and benzodiazepines lose their effect on dopamine neurons, ultimately leading to disinhibition of the dopamine neu-rons. The rewarding effects of benzodiazepines are, therefore, mediated by α1-containing GABAA receptors expressed on VTA neurons. Receptors containing α5 subunits seem to be required for tolerance to the sedative effects of benzodiazepines, and studies in humans link α2β3-containing receptors to alcohol dependence (the GABAA receptor is also a target of alcohol, see following text). Taken together, a picture is emerging linking GABAA receptors that contain the α1 subunit isoform to their addiction liability. By extension, α1-sparing compounds, which at present remain experimental and are not approved for human use, may eventually be preferred to treat anxiety disorders because of their reduced risk to induced addiction.
Alcohol (ethanol) 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.
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 recep-tors, Kir3/GIRK channels, adenosine reuptake (through the equili-brative 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 ces-sation. Generalized seizures may manifest after 24–48 hours. Finally, 48–72 hours after cessation, an alcohol withdrawal delir-ium (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 of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxaze-pam and lorazepam, which are not as dependent on hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longer-acting benzodiazepine such as chlordiazepoxide is preferred.
As in the treatment of all chronic drug abuse problems, heavy reli-ance 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.
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 appar-ent when patients undergoing surgery reported unpleasant vivid dreams and hallucinations after anesthesia. Ketamine and PCP are white crystalline powders in their pure forms, but on the street they are also sold as liquids, capsules, or pills, which can be snorted, ingested, injected, or smoked. Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory func-tion, 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.
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 house-hold and industrial products that are inhaled by “sniffing,” “huff-ing,” or “bagging.” Sniffing refers to inhalation from an open container, huffing to the soaking of a cloth in the volatile sub-stance 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 addic-tion 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 erec-tion, 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.