Proceedings of the National Academy of Sciences | 2019
β2* nAChRs on VTA dopamine and GABA neurons separately mediate nicotine aversion and reward
Abstract
Significance Nicotine addiction that results from long-term smoking is a worldwide health epidemic. Here we show that nicotinic receptors containing specific subunits, located in the brain reward system, mediate the experience of both the acute rewarding and aversive effects of nicotine, depending on which neurons they are located. These results provide contradictory evidence to the popularly held belief that the brain dopaminergic system exclusively mediates the rewarding effects of abused drugs, instead providing evidence that the aversive motivational effects of nicotine are signaled through this system as well. Our results lead to a better understanding of the neurobiological substrates of nicotine reward and aversion and thus may lead to new possible targets for pharmacotherapeutic treatments of tobacco addiction. 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.