Dopamine signaling through D1-like versus D2-like receptors in the nucleus accumbens core versus shell differentially modulates nicotine reward sensitivity.

Considerable evidence implicates the mesolimbic dopamine (DA) system in the processing of nicotine's reinforcing properties, specifically the ventral tegmental area (VTA) and the terminal fields of VTA DAergic projections to the "core" (NAcore) and "shell" (NAshell) subdivisions of the nucleus accumbens (NAc). However, the specific roles of DA D(1)-like and D(2)-like receptor subtypes in nicotine reward processing within these NAc subregions have not been elucidated. We report that microinfusions of DA D(1)-like or D(2)-like receptor-specific antagonists into NAcore or NAshell double dissociate the rewarding and aversive properties of systemic or intra-VTA nicotine, and differentially regulate sensitivity to the rewarding properties as well as the motivational valence of either intra-VTA or systemic nicotine administration. Using a place conditioning procedure, NAshell infusions of a D(2)-like receptor antagonist switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-reward threshold intra-VTA nicotine doses. In contrast, NAcore infusions of a D(1)-like receptor antagonist switched intra-VTA nicotine aversion to reward, and potentiated reward sensitivity to sub-reward threshold nicotine doses. Thus, D(1)-like versus D(2)-like receptors in NAcore versus NAshell subdivisions play functionally dissociable roles in modulating systemic or intra-VTA nicotine motivational processing.