a6 subunit-containing nicotinic receptors in alcohol consumption and reward

描述（由申请人提供）：饮酒是世界上导致过早死亡的第三大危险因素。对推动消费的作用机制的深入了解将有助于更好的戒酒治疗。酒精已经被证明可以激活中皮质边缘通路中的多巴胺能神经元，这是被所有其他已知滥用药物激活的主要大脑奖励回路。具体来说，尼古丁乙酰胆碱受体（nAChRs）与酒精消耗和奖励有关。神经元nachr是五聚体配体门控离子通道，具有12个不同的亚基（alpha2-alpha10, beta2-beta4）。亚基组成决定了受体的生物物理和药理学性质。nachr的亚基组成与酒精消耗和奖励有关，目前尚不清楚。之前，我们的实验室已经证明含有α 4亚基（α 4* nAChRs）的nachr在酒精消耗和奖励中起关键作用。此外，初步数据表明，涉及酒精消耗和奖励的nachr也可能含有α 6亚基。有趣的是，α - 6 nAChR亚基基因CHRNA6的多态性与人类饮酒者的大量饮酒有关。α 6亚基也在腹侧被盖区（VTA）的能神经元中高度表达，该区域是中皮质边缘通路的一部分。因此，我假设α 6* nachr与酒精消耗和奖励有关，也与能性VTA神经元的激活有关。为了验证这一假设，我将使用药理学、遗传学、电生理学和行为分析。在Aim 1中，我将在小鼠中脑切片中使用生物物理方法来验证α 6* nachr在乙醇诱导的VTA能神经元激活中起关键作用的假设。在Aim 2中，我将分别使用在黑暗中饮酒和条件反射位置偏好来衡量酒精消耗和奖励。这些试验将与脑区选择性输注α 6 nAChR拮抗剂和不表达CHRNA6的遗传小鼠模型结合进行。预计这些实验的结果将为深入了解急性酒精消耗和奖励的分子机制提供见解。

DESCRIPTION (provided by applicant): Alcohol consumption is the third largest risk factor for premature mortality in the world [1]. Insights into the mechanism of action that drives consumption will lead to better drinking cessation therapies. Alcohol has been shown to activate dopaminergic (DAergic) neurons within the mesocorticolimbic pathway, the major brain reward circuit activated by all other known drugs of abuse. Specifically, nicotinic acetylcholine receptor (nAChRs) have been implicated in alcohol consumption and reward. Neuronal nAChRs are pentameric ligand gated ion channels, with twelve distinct subunits identified (alpha2-alpha10, beta2-beta4). The subunit composition determines the biophysical and pharmacological properties of the receptor. Subunit composition of nAChRs involved in alcohol consumption and reward are currently unknown. Previously, our lab has shown that nAChRs that contain the alpha4 subunit (alpha 4* nAChRs) are critically involved in alcohol consumption and reward. In addition, preliminary data suggests that nAChRs involved in alcohol consumption and reward may also contain the alpha 6 subunit. Interestingly, there are polymorphisms in the alpha 6 nAChR subunit gene, CHRNA6, associated with heavy alcohol consumption in human drinkers [12]. The alpha 6 subunit is also highly expressed in DAergic neurons in the ventral tegmental area (VTA), which is part of the mesocorticolimbic pathway. Thus, I hypothesize that alpha 6* nAChRs are involved in alcohol consumption and reward, as well as activation of DAergic VTA neurons. To test this hypothesis, I will use pharmacology, genetics, electrophysiology and behavioral assays. In Aim 1, I will use biophysical approaches in mouse midbrain slices to test the hypothesis that alpha 6* nAChRs play a critical role in ethanol-induced activation of VTA DAergic neurons. In Aim 2, I will use drinking- in-the-dark and conditioned place preference to measure alcohol consumption and reward, respectively. These assays will be done in combination with brain region-selective infusions of alpha 6 nAChR antagonists and genetic mouse models that do not express CHRNA6. It is anticipated that the results from these experiments will provide insights into the molecular mechanism underlying acute alcohol consumption and reward.