Neuronal nicotine acetylcholine receptors and the response to alcohol

描述(由申请人提供)：酗酒与严重的短期和长期健康问题有关，包括判断力受损、情绪波动和心脏病。经常酗酒的酗酒者对酒精表现出更强的刺激性和奖赏反应。因此，了解酒精奖励和酗酒的分子基础应该有助于识别用于减少酒精消耗的治疗的新分子靶点。像尼古丁和其他滥用药物一样，酒精激活腹侧被盖区(VTA)的多巴胺(DA)能神经元，最终导致伏隔核(NAC)多巴胺(DA)浓度增加，这一现象广泛与药物的奖励或增强特性有关。以前，使用 结合神经元烟碱型乙酰胆碱受体(NAChR)小鼠模型、药理学、行为分析和电生理学，我们确定含有α4亚单位的nAChRs(表示为“alpha4*nAChRs”)，以前被发现在引发尼古丁依赖方面起着至关重要的作用，也与酒精和酗酒的回报特性有关。在前人研究的基础上，我们将检验这一假设，即腹侧被盖区(VTA)中的α4*nAChRs特异性地参与酒精奖赏、消费和酒精介导的VTA多巴胺能(DAERARY)神经元的激活。这一假说将通过病毒介导的基因传递在阿尔法4基因敲除(KO)小鼠的VTA中特异性地重新表达，并与对照KO小鼠相比，测量酒精奖励、酗酒和酒精介导的VTA DA能神经元的激活来验证这一假说。此外，对激动剂高度敏感的α4亚基将选择性地在VTA内不同的神经元亚群中表达，以确定VTA微回路中nAChR的表达如何影响酒精奖励和急性消费。在目标2中，我们将使用分子和生物物理方法来验证乙醇介导的DAR能VTA神经元的激活也涉及含有α6亚单位的nAChRs的假设。最后，Aim 3将结合小鼠遗传学和药理学，确定α6*nAChRs如何参与酒精奖赏和饮酒。预计这些实验的结果将对酒精奖励和酗酒的分子基础产生有价值的见解，并确定戒酒治疗的潜在靶点。

DESCRIPTION (provided by applicant): Binge drinking is associated with significant short- and long-term health problems including impaired judgment, mood swings, and heart disease. Heavy alcohol users who frequently binge drink exhibit increased stimulant and rewarding responses to alcohol. Thus, understanding the molecular bases of alcohol reward and binge drinking should lead to identification of novel molecular targets for therapeutics designed to decrease alcohol consumption. Like nicotine and other drugs of abuse, alcohol activates dopaminergic (DAergic) neurons in the ventral tegmental area (VTA), which ultimately yields an increase in dopamine (DA) concentrations in the nucleus accumbens (NAc), a phenomenon widely associated with the rewarding or reinforcing properties of the drug. Previously, utilizing a combination of neuronal nicotinic acetylcholine receptor (nAChR) mouse models, pharmacology, behavioral assays, and electrophysiology, we determined that nAChRs containing the alpha4 subunit (denoted "alpha4* nAChRs"), previously found to be paramount in initiating nicotine dependence, are also involved in the rewarding properties of ethanol and binge drinking. Building upon previous studies, we will test the hypothesis that alpha4* nAChRs specifically in the ventral tegmental area (VTA) contribute to alcohol reward, consumption, and alcohol-mediated activation of VTA dopaminergic (DAergic) neurons. This hypothesis will be tested by re-expressing alpha4 nAChR subunits specifically in the VTA of alpha4 knock- out (KO) mice via viral-mediated gene delivery and measuring alcohol reward, binge drinking, and alcohol-mediated activation of VTA DAergic neurons compared to control KO mice. In addition, alpha4 subunits that are hypersensitive to agonist will be expressed selectively in distinct neuronal subpopulations within the VTA to determine how nAChR expression within VTA micro-circuitry affects alcohol reward and acute consumption. In aim 2, we will use molecular and biophysical approaches to test the hypothesis that ethanol-mediated activation of DAergic VTA neurons also involves nAChRs that contain the alpha6 subunit. Finally, aim 3 will determine how alpha6* nAChRs are involved in alcohol reward and consumption using a combination of mouse genetics and pharmacology. It is anticipated that the results from these experiments will yield valuable insight into the molecular underpinnings of alcohol reward and binge drinking, as well as identify potential targets for alcohol cessation therapeutics.