β2* nAChRs on VTA dopamine and GABA neurons separately mediate nicotine aversion and reward

Abstract

Evidence shows that the neurotransmitter dopamine mediates the rewarding effects of nicotine and other drugs of abuse, while nondopaminergic neural substrates mediate the negative motivational effects. β2* nicotinic acetylcholine receptors (nAChR) are necessary and sufficient for the experience of both nicotine reward and aversion in an intra-VTA (ventral tegmental area) self-administration paradigm. We selectively reexpressed β2* nAChRs in VTA dopamine or VTA γ-amino-butyric acid (GABA) neurons in β2−/− mice to double-dissociate the aversive and rewarding conditioned responses to nicotine in nondependent mice, revealing that β2* nAChRs on VTA dopamine neurons mediate nicotine’s conditioned aversive effects, while β2* nAChRs on VTA GABA neurons mediate the conditioned rewarding effects in place-conditioning paradigms. These results stand in contrast to a purely dopaminergic reward theory, leading to a better understanding of the neurobiology of nicotine motivation and possibly to improved therapeutic treatments for smoking cessation.