Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2*Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement
Nicotinic Acetylcholine Receptors in the Mesolimbic Pathway: Primary Role of Ventral Tegmental Area α6β2*Receptors in Mediating Systemic Nicotine Effects on Dopamine Release, Locomotion, and Reinforcement
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DOI：
10.1523/jneurosci.5095-09.2010
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发表时间：
2010-04-14
影响因子：
5.3
通讯作者：
Zoli, Michele
中科院分区：
文献类型：
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作者：
Gotti, Cecilia;Guiducci, Stefania;Zoli, Michele
α 6*烟碱乙酰胆碱受体（nAChRs）在中纹状体多巴胺（DA）神经元中高度选择性表达。这些神经元被认为介导尼古丁的几种行为效应，包括运动、习惯学习和强化。然而，α 6* nachr在中脑DA神经元中的功能作用尚不清楚。本研究旨在探讨雄性大鼠中边缘DA神经元α 6* nAChR的组成及其在体内的功能作用。免疫沉淀和免疫纯化技术结合细胞特异性病变显示，中纹状体系统中α 6* nAChR的组成是不均匀的，（非α 4） α 6 β 2*主要存在于中边缘通路，α 4 α 6 β 2*主要存在于黑质纹状体通路。我们通过将α - concontoxin MII (CntxMII) （α 3/ α 6 β 2*选择性）或α - concontoxin PIA (CntxPIA) （α 6 β 2*选择性）灌注到腹侧被皮层（VTA），验证α 6*受体是否介导尼古丁对中脑边缘DA通路的全身性影响。vta内灌注CntxMII或CntxPIA显著降低伏隔核全身性尼古丁诱导的darelease和习惯性运动；vta内灌注CntxMII也能降低尼古丁维持期的尼古丁输注率，但对食物、自我给药没有影响。总的来说，这些实验结果表明，VTA中表达的α 6 β 2* nachr对于尼古丁对DA神经元活动和DA依赖行为（如运动和强化）的影响是必要的，并且表明能够穿过血脑屏障的α 6 β 2*选择性化合物可能影响尼古丁的成瘾特性，因此在烟草依赖的治疗中是有用的。
alpha 6* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of alpha 6* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of alpha 6* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of alpha 6* nAChR in the mesostriatal system is heterogeneous, with (non-alpha 4)alpha 6 beta 2* being predominant in the mesolimbic pathway and alpha 4 alpha 6 beta 2* in the nigrostriatal pathway. We verified whether alpha 6* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists alpha-conotoxin MII (CntxMII) (alpha 3/alpha 6 beta 2* selective) or alpha-conotoxin PIA (CntxPIA) (alpha 6 beta 2* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicitedDArelease in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the alpha 6 beta 2* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that alpha 6 beta 2*-selective compounds capable of crossing the blood-brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence.