Nicotine is a selective agonist of the nicotinic acetylcholine receptor (nAChR) that is normally activated by acetylcholine (see Chapters 6 and 7). Based on nicotine’s enhancement of cognitive performance and the association of Alzheimer’s dementia with a loss of ACh-releasing neurons from the nucleus basalis of Meynert, nAChRs are believed to play an important role in many cognitive processes. The rewarding effect of nicotine requires involvement of the VTA, in which nAChRs are expressed on dopamine neurons. When nicotine excites projection neurons, dopamine is released in the nucleus accumbens and the prefrontal cortex, thus fulfilling the dopamine requirement of addictive drugs. Recent work has identified 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 transfection 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 excitatory afferents projecting onto the dopamine neurons. They also contribute to nicotine-evoked dopamine release and the long-term changes induced by the drugs related to addiction (eg, long-term synaptic potentiation of excitatory inputs).
Nicotine withdrawal is mild compared with opioid withdrawal and involves irritability and sleep problems. However, nicotine is among the most addictive drugs (relative risk 4), and relapse after attempted cessation is very common.
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 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 are commonly prescribed as anxiolytics and sleep medications. They represent a definite risk for abuse, which has to be weighed against their beneficial effects. Some persons abuse benzodiazepines for their euphoriant effects, but most often abuse occurs concomitant with other drugs, eg, to attenuate anxiety during withdrawal from opioids.
Benzodiazepine dependence is very common, and diagnosis of addiction is probably often missed. 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, phonophobia and photophobia, depression, muscle cramps, and even seizures. Typically, these symptoms taper off within 1–2 weeks.