Institute of Medical Science, University of Toronto, Toronto, ON M5S 3E1, Canada;
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada.
Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25968-25973. doi: 10.1073/pnas.1908724116. Epub 2019 Nov 27.
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.
证据表明，神经递质多巴胺介导尼古丁和其他成瘾药物的奖赏效应，而非多巴胺能神经基质则介导负性动机效应。β2烟碱型乙酰胆碱受体（nAChR）对于腹侧被盖区（VTA）内自我给药范式中尼古丁奖赏和厌恶的体验是必需且充分的。我们在β2 小鼠的 VTA 多巴胺或 VTA γ-氨基丁酸（GABA）神经元中选择性地重新表达β2nAChR，以在非依赖性小鼠中双重分离尼古丁的厌恶和奖赏条件反应，揭示 VTA 多巴胺神经元上的β2nAChR 介导尼古丁的条件性厌恶效应，而 VTA GABA 神经元上的β2nAChR 则在条件性位置范式中介导条件性奖赏效应。这些结果与纯粹的多巴胺奖赏理论形成对比，从而更好地理解尼古丁动机的神经生物学，并可能为戒烟治疗提供更好的治疗方法。
