Cellular mechanisms of nicotine addiction.

In developed countries, tobacco use is estimated to be the largest single cause of premature death [Lancet 339 (1992) 1268]. Nicotine is the main addictive component of tobacco that motivates continued use despite the harmful effects. Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the mammalian central nervous system (CNS), where they normally respond to acetylcholine (ACh) and modulate neuronal excitability and synaptic communication. Nicotinic receptors are structurally diverse and have varied roles. Presynaptic and preterminal nAChRs enhance neurotransmitter release. Postsynaptic and somal nAChRs mediate a small proportion of fast excitatory transmission and modulate cytoplasmic second messenger systems. Although the impact of nicotine obtained from tobacco is not completely understood, a portion of nicotine's addictive power is attributable to actions upon the dopaminergic systems, which normally help to reinforce rewarding behaviors. As obtained from tobacco, nicotine activates and desensitizes nAChRs, and both processes contribute to the cellular events that underlie nicotine addiction.