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).