α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity.
α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity.
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DOI：
10.1016/j.neuroscience.2015.07.052
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发表时间：
2015-09-24
期刊：
影响因子：
3.3
通讯作者：
Drenan RM
中科院分区：
文献类型：
--
作者：
Berry JN;Engle SE;McIntosh JM;Drenan RM
乙酰胆碱通过腹侧中脑和纹状体的烟碱型和毒蕈碱型乙酰胆碱（ACh）受体影响多巴胺（DA）的传递。这种多巴胺传递的胆碱能控制对于注意力和动机行为等过程很重要，并且受到烟草产品中尼古丁的操纵。识别和表征参与DA传递的胆碱能控制的关键ACh受体可能导致用于治疗涉及注意力、成瘾、帕金森病和精神分裂症的疾病的小分子疗法。α 6烟碱型乙酰胆碱受体（nAChRs）在中脑DA神经元中高度特异性表达，使其成为一个有吸引力的药物靶点。在这里，我们使用遗传学，药理学，行为学和生物物理学的方法来研究这种nAChR亚型。在许多实验中，我们使用表达突变型α 6 nAChR的小鼠（"α 6L9S"小鼠），这些突变型α 6 nAChR增加了这些受体对激动剂（如ACh和尼古丁）的敏感性。利用α 6 L9S小鼠表现出的简单行为表型，我们比较了完全与部分α 6 * nAChR激动剂在体内激活α 6 * nAChR的能力。使用局部输注的激动剂和拮抗剂到大脑中，我们证明，在中脑的神经元和nAChRs是足以解释这种行为反应。为了补充这些行为研究，我们研究了体内α 6 * nAChR激活支持中脑DA神经元可塑性变化的能力，这些变化与行为敏化和成瘾有关。通过结合局部药物灌注和脑片膜片钳电生理学，我们发现激活中脑DA区域的α 6 * nAChRs足以增强VTA DA神经元的多巴胺能传递。总之，体内研究的这些结果强烈表明，腹侧被盖区DA神经元表达的α 6 * nAChR能够强烈影响DA介导的行为和尼古丁诱导的突触可塑性。
Acetylcholine acts through nicotinic and muscarinic acetylcholine (ACh) receptors in ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson’s disease, and schizophrenia. α6-containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs (“α6L9S” mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6* nAChR agonists to activate α6* nAChRs in vivo. Using local infusions of both agonists and antagonists into brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6* nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch clamp electrophysiology, we show that activating α6* nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in VTA DA neurons. Together, these results from in vivo studies strongly suggest that α6* nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine.