NICOTINE ACTIVATES AND DESENSITIZES MIDBRAIN DOPAMINE NEURONS

Tobacco use in developed countries is estimated to be the single large st cause of premature death(1), Nicotine is the primary component of t obacco that drives use, and like other addictive drugs, nicotine reinf orces self-administration and place preference in animal studies(2-5). Midbrain dopamine neurons normally help to shape behaviour by reinfor cing biologically rewarding events, but addictive drugs such as cocain e can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system(3-6). Here we show that the same concentra tion of nicotine achieved by smokers activates and desensitizes multip le nicotinic receptors thereby regulating the activity of mesolimbic d opamine neurons, Initial application of nicotine can increase the acti vity of the dopamine neurons, which could mediate the rewarding aspect s of tobacco use, Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic recep tors, which helps to explain acute tolerance to nicotine's effects, Th e effects suggest a cellular basis for reports that the first cigarett e of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensi tization of multiple nicotinic receptors(5).