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

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. beta 2* 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 beta 2* nAChRs in VTA dopamine or VTA gamma-amino-butyric acid (GABA) neurons in beta 2(-/-) mice to double-dissociate the aversive and rewarding conditioned responses to nicotine in nondependent mice, revealing that beta 2* nAChRs on VTA dopamine neurons mediate nicotine's conditioned aversive effects, while beta 2* 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.