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

基本信息

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
项目类别：
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

项目摘要

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，并以高度合并症表示。饮酒后的反复戒断周期可能会导致调节酒精饮酒和与焦虑相关行为的大脑区域的持续适应，包括杏仁核（CEA）的中心核（CEA）和Stria terminalis（BNST）的床核（BNST）在扩展的杏仁核中。这些变化会导致压力反应失调，焦虑水平增加和复发行为。神经肽Y（NPY）信号传导是一种内源性神经化学系统，可调节酒精饮酒和与焦虑有关的行为。 NPY Y1受体（Y1R）的激活会产生行为焦虑症并降低乙醇的消耗，而Y2受体（Y2R）激活会产生行为焦虑生成并增加乙醇的消耗。尽管有证据表明，通过调节BNST中的抑制性突触传播，可能会发生Y2R介导的NPY效应，但仍然缺乏对Y1R特异性NPY信号传导的详细机械理解。此外，重复接触酒精可能会导致NPY信号传导失调和随后的行为改变，尽管发生这种情况的具体机制是较少了解的。因此，该提案的总体目标是1）表征Y1R介导的信号传导对小鼠BNST中抑制性突触传播的影响； 2）确定慢性酒精自我给药对Y1R和Y2R Y2R特异性NPY信号的急性和延伸作用。了解内源性NPY系统的机制可能有助于治疗焦虑症和酒精中毒。我假设慢性自愿饮酒会导致BNST中受体特异性NPY信号的失调，最终表现在饮酒和与焦虑相关的行为改变。