The effect of alcohol drinking on NPY modulation of inhibition in the BNST

饮酒对 BNST 中 NPY 抑制调节的影响

• 批准号: 8314809
• 负责人: Kristen Elizabeth Pleil
• 金额: $ 4.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314809
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral; Brain Part; Brain region; Buffers; Calcium; Cell Nucleus; Chronic; Comorbidity; Data; Electrophysiology (science); Future; Goals; Hour; Immunohistochemistry; Lead; Link; Literature; Long-Term Effects; Macaca mulatta; Measures; Mediating; Mental Depression; Molecular; Mus; Neural Pathways; Neuropeptide Y Receptor; Pharmacological Treatment; Property; Publishing; Receptor Activation; Regulation; Relapse; Rodent; Self Administration; Signal Transduction; Site; Social Interaction; Societies; Stress; Structure of terminal stria nuclei of preoptic region; Substrate Interaction; Synapses; Synaptic Transmission; System; Testing; Withdrawal; alcohol exposure; approach behavior; biological adaptation to stress; drinking; drinking behavior; gamma-Aminobutyric Acid; in vivo; neural circuit; neurochemistry; neuropeptide Y; neuropeptide Y-Y1 receptor; nonhuman primate; novel; optogenetics; presynaptic; receptor; receptor expression; receptor function; receptor-mediated signaling; resilience; social; therapeutic target; transmission process

Alcohol abuse and anxiety disorders are prevalent in our society and are expressed with a high degree of comorbidity. Repeated cycles of withdrawal after binge alcohol drinking may cause persistent adaptations in brain regions that regulate alcohol drinking and anxiety-related behaviors, including the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the extended amygdala. These changes can lead to a dysregulated stress response, increased levels of anxiety, and relapse behavior. Neuropeptide Y (NPY) signaling is one endogenous neurochemical system that modulates alcohol drinking and anxiety-related behaviors. Activation of the NPY Y1 receptor (Y1R) produces behavioral anxiolysis and decreases ethanol consumption, while Y2 receptor (Y2R) activation produces behavioral anxiogenesis and increases ethanol consumption. While there is evidence that Y2R-mediated effects of NPY may occur via modulation of inhibitory synaptic transmission in the BNST, there remains a lack of a detailed mechanistic understanding of Y1R-specific NPY signaling. In addition, repeated exposure to alcohol may lead to dysregulation of NPY signaling and subsequent alterations in behavior, though the specific mechanisms by which this occurs are poorly understood. Therefore, the overarching goals of this proposal are to 1) characterize the effect of Y1R-mediated signaling on inhibitory synaptic transmission in the mouse BNST and 2) determine the acute and protracted effects of chronic alcohol self-administration on Y1R and Y2R-specific NPY signaling in the BNST of mice and rhesus monkeys. Understanding the mechanisms of the endogenous NPY system may be useful for treating both anxiety disorders and alcoholism. I hypothesize that chronic voluntary alcohol drinking leads to dysregulation of receptor-specific NPY signaling in the BNST, which is ultimately manifested in altered alcohol drinking and anxiety-related behaviors.

酒精滥用和焦虑症在我们的社会中很普遍，并且表现出高度的共病性。酗酒后反复的戒断循环可能会导致调节饮酒和焦虑相关行为的大脑区域的持续适应，包括杏仁核中央核（CeA）和延伸杏仁核中的终纹床核（BNST）。这些变化可能导致压力反应失调，焦虑水平增加和复发行为。神经肽Y（neuropeptide Y，NPY）信号是一种调节饮酒和焦虑相关行为的内源性神经化学系统。NPY Y1受体（Y1 R）的激活产生行为性抗焦虑并减少乙醇消耗，而Y2受体（Y2 R）的激活产生行为性抗焦虑并增加乙醇消耗。虽然有证据表明，Y2 R介导的作用，可能会发生通过调制抑制性突触传递的BNST，仍然缺乏一个详细的机制的理解Y1 R特异性NPY信号。此外，反复暴露于酒精可能会导致神经肽Y信号的失调和随后的行为改变，尽管这种情况发生的具体机制知之甚少。因此，本提案的总体目标是：1）表征Y1 R介导的信号传导对小鼠BNST中抑制性突触传递的影响; 2）确定长期酒精自我给药对小鼠和恒河猴BNST中Y1 R和Y2 R特异性NPY信号传导的急性和长期影响。了解内源性神经肽Y系统的机制可能有助于治疗焦虑症和酒精中毒。我推测，慢性自愿饮酒导致BNST中受体特异性NPY信号转导失调，最终表现为饮酒和焦虑相关行为的改变。