bodies. Many animal studies have also demonstrated that nicotine administration upregulates expression of nAchRs in the brain. Similarly, ligand-binding studies have demonstrated an increase in binding sites for nicotine analogues in the cerebral cortex and hippocampus of smokers compared to nonsmokers (Perry et al., 1999), although the extent to which this may contribute to the differential central effects of nicotine observed in smokers is unknown.

Dopamine is believed to be the dominant neurotransmitter in the maintenance of drug-taking behavior (DiChiara, 1999; Koob, 1992). The area of the brain that is responsible for the reinforcing effects of all drugs of abuse is the mesolimbic pathway, which contains the ventral tegmental area (VTA), nucleus accumbens, amygdala, cingulate gyrus, and frontal lobe and is rich in dopamine. The VTA and nucleus accumbens seem particularly important in nicotine’s reinforcing effects. Activation of nAchRs in the VTA and other parts of the midbrain, modulates the ascending mesolimbic dopamine system, including the nucleus accumbens (George et al., 2000; Yu et al., 2000). Nicotine self-administration behavior is diminished by either surgical or chemical ablation of dopaminergic pathways or by treatment with dopamine antagonists (Kameda et al., 2000). Nicotine evokes an increase in dopamine levels in brain microdialysis studies (Fu et al., 2000). In addition, monoamine oxidase A and B, responsible for the metabolism of dopamine, are reduced by a compound in tobacco smoke that also results in higher levels of neurotransmitters (Quattrocki et al., 2000).

The release or inhibition of other transmitters may also play a role in nicotine addiction. They may be responsible for mood modulation, the modest enhancement of performance, and the weight-reducing effects of nicotine (Benowitz, 1999; Chiodera et al., 1990; Chowdhury et al., 1989; U.S. DHHS, 1988). Mood modulation by nicotine has been a controversial topic, since laboratory studies do not validate the smoking-induced enhancement of mood self-reported by smokers. Furthermore, individuals experience greater positive affect when smoking after a period of abstinence. The relief of negative affect by tobacco use may be more a function of abating withdrawal symptoms (Cinciripini et al., 1997; RCP, 2000). Finally, in addition to its traditional pre- and postsynaptic actions at synapses and at chemoreceptors in the carotid and aortic bodies, nicotine also evokes the release of epinephrine from the adrenal medulla and may act directly to activate ion channels distinct from nAchRs. For example, nicotine has been shown to block directly inward rectifier potassium channels, an effect of potential relevance to cardiac arrhythmogenesis (Wang et al., 2000b).



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