Chronic nicotine exposure switches the functional role of mesolimbic dopamine transmission in the processing of nicotine's rewarding and aversive effects.

The mammalian ventral tegmental area (VTA) and associated mesolimbic dopamine (DA) system are critical neural substrates for processing nicotine's motivational effects. Considerable evidence suggests that the role of DA transmission may be altered as a function of nicotine exposure. Using a combination of in vivo neuronal recording and behavioral conditioning, we report that chronic nicotine exposure induces a functional switch in the role of mesolimbic DA transmission. Thus, in nicotine-naive subjects, blockade of DA transmission potentiates the rewarding effects of sub-reward-threshold doses of nicotine and reverses the motivational valence of nicotine from aversive to rewarding. However, in animals treated chronically with nicotine, DA blockade switches previously sub-reward-threshold or rewarding doses of nicotine into aversion signals. Neuronal VTA recordings similarly revealed a functional switch in this DAergic neuronal circuit resulting in strongly increased sensitivity of the VTA DAergic system to nicotine administration and a tonic reduction in the baseline activity of VTA DAergic neurons. These results demonstrate a functional switch in the role of DAergic transmission during the acute versus chronic phases of nicotine exposure and suggest that mesolimbic DA transmission plays qualitatively distinct roles in the processing of nicotine's motivational effects as a function of drug exposure.