Page 598 - Basic _ Clinical Pharmacology ( PDFDrive )

584 SECTION V Drugs That Act in the Central Nervous System

Nicotine is a selective agonist of the nicotinic acetylcholine benzodiazepines for their euphoriant effects, but most often abuse
receptor (nAChR) that is normally activated by acetylcholine (see occurs concomitant with other drugs, eg, to attenuate anxiety dur-
Chapters 6 and 7). Based on nicotine’s enhancement of cognitive ing withdrawal from opioids.
performance and the association of Alzheimer’s dementia with a Benzodiazepine dependence is very common, and diagnosis of
loss of ACh-releasing neurons from the nucleus basalis of Meynert, addiction is probably often missed. Withdrawal from benzodiaz-
nAChRs are believed to play an important role in many cognitive epines occurs within days of stopping the medication and varies
processes. The rewarding effect of nicotine requires involvement of as a function of the half-life of elimination. Symptoms include
the VTA, in which nAChRs are expressed on dopamine neurons. irritability, insomnia, phonophobia and photophobia, depression,
When nicotine excites projection neurons, dopamine is released in muscle cramps, and even seizures. Typically, these symptoms taper
the nucleus accumbens and the prefrontal cortex, thus fulfilling the off within 1–2 weeks.
dopamine requirement of addictive drugs. Recent work has identi- Benzodiazepines are positive modulators of the GABA recep-
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fied α4β2-containing channels in the VTA as the nAChRs that tor, increasing both single-channel conductance and open-channel
are required for the rewarding effects of nicotine. This statement is probability. GABA receptors are pentameric structures consisting
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based on the observation that knockout mice deficient for the β2 of α, β, and γ subunits (see Chapter 22). GABA receptors on
subunit lose interest in self-administering nicotine, and that in these dopamine neurons of the VTA lack α1, a subunit isoform that
mice, this behavior can be restored through an in vivo transfec- is present in GABA neurons nearby (ie, interneurons). Because
tion of the β2 subunit in neurons of the VTA. Electrophysiologic of this difference, unitary synaptic currents in interneurons are
evidence suggests that homomeric nAChRs made exclusively of α7 larger than those in dopamine neurons, and when this difference
subunits also contribute to the reinforcing effects of nicotine. These is amplified by benzodiazepines, interneurons fall silent. GABA is
receptors are mainly expressed on synaptic terminals of excitatory no longer released, and benzodiazepines lose their effect on dopa-
afferents projecting onto the dopamine neurons. They also contrib- mine neurons, ultimately leading to disinhibition of the dopamine
ute to nicotine-evoked dopamine release and the long-term changes neurons. The rewarding effects of benzodiazepines are, therefore,
induced by the drugs related to addiction (eg, long-term synaptic mediated by α1-containing GABA receptors expressed on VTA
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potentiation of excitatory inputs). neurons. Receptors containing α5 subunits seem to be required
Nicotine withdrawal is mild compared with opioid withdrawal for tolerance to the sedative effects of benzodiazepines, and studies
and involves irritability and sleep problems. However, nicotine is in humans link α2β3-containing receptors to alcohol dependence
among the most addictive drugs (relative risk 4), and relapse after (the GABA receptor is also a target of alcohol, see following text).
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attempted cessation is very common. Taken together, a picture is emerging linking GABA receptors
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that contain the α1 subunit isoform to their addiction liability.
Treatment By extension, α1-sparing compounds, which at present remain
experimental and are not approved for human use, may eventually
Treatments for nicotine addiction include nicotine itself in forms that be preferred to treat anxiety disorders because of their reduced risk
are slowly absorbed and several other drugs. Nicotine that is chewed, of induced addiction.
inhaled, or transdermally delivered can be substituted for the nicotine Barbiturates, which preceded benzodiazepines as the most
in cigarettes, thus slowing the pharmacokinetics and eliminating the commonly abused sedative-hypnotics (after ethanol), are now
many complications associated with the toxic substances found in rarely prescribed to outpatients and therefore constitute a less
tobacco smoke. Recently, two partial agonists of α4β2-containing common prescription drug problem than they did in the past.
nAChRs have been characterized: the plant-extract cytisine and its Street sales of barbiturates, however, continue. Management
synthetic derivative varenicline. Both work by occupying nAChRs of barbiturate withdrawal and addiction is similar to that of
on dopamine neurons of the VTA, thus preventing nicotine from benzodiazepines.
exerting its action. Varenicline may impair the capacity to drive and
has been associated with suicidal ideation. The antidepressant bupro-
pion is approved for nicotine cessation therapy. It is most effective ALCOHOL
when combined with behavioral therapies.
Many countries have banned smoking in public places to create Alcohol (ethanol, see Chapter 23) is regularly used by a majority
smoke-free environments. This important step not only reduces of the population in many Western countries. Although only a
passive smoking and the hazards of secondhand smoke, but also minority becomes dependent and addicted, abuse is a very seri-
the risk that ex-smokers will be exposed to smoke, which as a ous public health problem because of the social costs and many
contextual cue, may trigger relapse. diseases associated with alcoholism.

BENZODIAZEPINES Pharmacology
The pharmacology of alcohol is complex, and no single receptor
Benzodiazepines are commonly prescribed as anxiolytics and sleep mediates all of its effects. On the contrary, alcohol alters the func-
medications. They represent a definite risk for abuse, which has tion of several receptors and cellular functions, including GABA A
to be weighed against their beneficial effects. Some persons abuse receptors, Kir3/GIRK channels, adenosine reuptake (through