We have read with interest the report in the ARCHIVES by Prochazka et al1 documenting that the antidepressant nortriptyline may represent a new therapeutic approach to smoking cessation. We would like to provide some additional considerations.
Nicotine is a highly addictive substance2,3 that exerts a number of neurovegetative, behavioral, and psychological effects by interacting with neuronal nicotinic acetylcholine receptors.4 Functional magnetic resonance imaging has shown that nicotine induces an increased neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes, that participate in reinforcing mood-elevating and cognitive properties of other abuse substances.5 It is hypothesized that increases in nicotinic receptor levels underlie addiction in smokers, and thus, these receptors are suitable potential targets for drug therapy. Indeed, long-term administration of nicotine evokes, in animal models but also in humans, a dose-dependent increase in brain nicotinic receptor number and binding6,7 that is reversed within 1 week after withdrawal.8 Conversely, the blockade of nicotinic receptors seems to produce antiaddictive effects. For example, in an intervention trial, nicotine skin patches plus mecamylamine, a nicotinic antagonist, have been shown to facilitate smoking cessation, thereby improving abstinence and reducing the craving, negative affect, and appetite of heavy smokers.9 In addition, chlorisondamine, a quaternary nicotinic antagonist, induces a long-term blockade of the rewarding effects of nicotine.10
Gambassi G, Bernabei R. Antidepressants and Smoking Cessation. Arch Intern Med. 1999;159(11):1254. doi:
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