α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.
α4β2 nicotinic acetylcholine receptors on dopaminergic neurons mediate nicotine reward and anxiety relief.
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DOI：
10.1523/jneurosci.0937-11.2011
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发表时间：
2011-07-27
期刊：
影响因子：
--
通讯作者：
Booker TK
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文献类型：
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作者：
McGranahan TM;Patzlaff NE;Grady SR;Heinemann SF;Booker TK
尼古丁是烟草中的主要精神活性物质，它通过与大脑中烟碱乙酰胆碱受体（nAChR）的各种亚型相互作用发挥其作用。在脑中表达的主要亚型之一，α 4 β 2-nAChR，内源性调节神经元兴奋性，从而改变某些正常以及尼古丁诱导的行为。虽然含有α 4的nAChR在整个大脑中广泛表达，但主要关注的是它们在中脑多巴胺能区域中的作用，这些区域涉及人类的药物添加，精神疾病和运动控制。我们开发了一种独特的模型系统，通过从小鼠多巴胺能神经元中靶向基因缺失α 4亚基来检查α 4-nAChRs在多巴胺能神经元中的作用。证实了多巴胺能神经元的α 4 mRNA和α 4 β 2-nAChR的损失，以及多巴胺能神经元而非GABA能神经元的α 4 β 2-nAChR功能的选择性损失。尼古丁依赖的两个核心行为，奖励和焦虑缓解，进行了检查。多巴胺能神经元上特异性的α 4-nAChR被证明是尼古丁奖赏所必需的，如通过尼古丁位置偏好所测量的，但不是另一种成瘾药物可卡因。在高架十字迷宫中，α 4-nAChR对于尼古丁的抗焦虑作用是必需的，并且特异性地从多巴胺能神经元消除α 4-β 2-nAChR降低了对尼古丁的抗焦虑作用的敏感性。从多巴胺能神经元特异性地删除α 4-nAChRs也增加了对尼古丁诱导的运动抑制的敏感性，但是尼古丁诱导的体温过低不受影响。这是第一个开发多巴胺能特异性缺失nAChR亚基并检查尼古丁行为变化的工作。
Nicotine is the primary psychoactive substance in tobacco and it exerts its effects by interaction with various subtypes of nicotinic acetylcholine receptors (nAChRs) in the brain. One of the major subtypes expressed in brain, the alpha4beta2-nAChR, endogenously modulates neuronal excitability and thereby, modifies certain normal, as well as nicotine-induced, behaviors. Although alpha4-containing nAChRs are widely expressed across the brain, a major focus has been on their roles within midbrain dopaminergic regions involved in drug addition, mental illness and movement control in humans. We developed a unique model system to examine the role of alpha4-nAChRs within dopaminergic neurons by a targeted genetic deletion of the alpha4 subunit from dopaminergic neurons in mice. The loss alpha4 mRNA and alpha4beta2-nAChRs from dopaminergic neurons was confirmed, as well as selective loss of alpha4beta2-nAChR function from dopaminergic but not GABAergic neurons. Two behaviors central to nicotine dependence, reward and anxiety relief, were examined. Alpha4-nAChRs specifically on dopaminergic neurons were demonstrated to be necessary for nicotine reward as measured by nicotine place preference, but not for another drug of addiction, cocaine. Alpha4-nAChRs are necessary for the anxiolytic effects of nicotine in the elevated plus maze and elimination of alpha4-beta2-nAChRs specifically from dopaminergic neurons decreased sensitivity to the anxiolytic effects of nicotine. Deletion of alpha4-nAChRs specifically from dopaminergic neurons also increased sensitivity to nicotine-induced locomotor depression, however nicotine-induced hypothermia was unaffected. This is the first work to develop a dopaminergic specific deletion of a nAChR subunit and examine resulting changes in nicotine behaviors.