Stress and Ethanol Dependence: SK Channels and Glutamate

压力和乙醇依赖性：SK 通道和谷氨酸

基本信息

批准号：
8424260
负责人：
PATRICK J. MULHOLLAND
金额：
$ 17.08万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2012-02-10 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8424260
关键词：
Action Potentials Adrenal Glands Affect Alcohol abuse Alcohol consumption Alcohol dependence Alcohols Apamin Biochemical Brain Brain region Calcium Chronic Chronic stress Cognitive Complement Consumption Data Dependence Down-Regulation Ethanol Ethanol dependence Exposure to Feedback Functional disorder Glutamates Heavy Drinking Hippocampus (Brain)Hypothalamic structure Image Laboratories Lead Link Medial Mediating Mediator of activation protein Microinjections Molecular Mus N-Methyl-D-Aspartate Receptors Neurons Nucleus Accumbens Pacemakers Pathway interactions Pattern Pharmaceutical Preparations Pituitary Gland Prefrontal Cortex Protocols documentation Relapse Role SK potassium channel Signal Transduction Stress Structure Synapses Synaptic plasticity Techniques Testing Vertebral column Water consumption Withdrawal alcohol exposure alcohol seeking behavior alcoholism therapy density drinking drinking behavior drug seeking behavior hippocampal pyramidal neuron hypothalamic-pituitary-adrenal axis innovation insight neuroadaptation neurochemistry new therapeutic target novel postsynaptic response synaptic function

项目摘要

DESCRIPTION (provided by applicant): Heavy alcohol drinking and repeated withdrawals are associated with increased relapse and allostatic adaptations in the hypothalamic-pituitary-adrenal (HPA) axis. Excessive alcohol intake is also associated with perturbations in cortico-limbic-HPA function that may contribute to alcohol dependence and high rates of relapse. Our preliminary evidence suggests that a critical modulator of high rates of voluntary drinking in alcohol-dependent mice is the small-conductance calcium-activated potassium (SK) channels. SK channels in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) regulate NMDA receptor-dependent calcium influx, intrinsic excitability, and basal firing rates. Results from our preliminary studies demonstrate that SK channel expression is significantly reduced in mPFC and NAc in C57BL/6J mice following chronic intermittent ethanol (CIE) exposure or prolonged stress. Moreover, microinjection studies show that blocking SK channel activity in NAc enhances voluntary consumption in control, but not alcohol-dependent mice. These data suggest that the down-regulation of SK channels observed following CIE is critically involved in the escalation of drinking in CIE exposed mice. Thus, the overarching hypothesis of this proposal is that CIE increases the excitation at glutamatergic synapses through a combination of increased NMDA receptors and a decrease in SK channel activity in key brain regions that control drinking. These studies will test the hypotheses that: 1) chronic ethanol exposure and stress alter glutamatergic synapses, 2) divergent drinking patterns in genetically modified mice are linked to alterations in SK channel expression, and 3) SK channels in mPFC and NAc regulate escalation of drinking in CIE exposed mice. We expect that data collected from these studies will advance our understanding of synaptic plasticity in key brain regions involved in alcohol seeking behaviors and will validate the hypothesis that SK channels are an important new therapeutic target for the treatment of alcohol dependence.

描述（由申请人提供）：大量饮酒和反复戒酒与下丘脑-垂体-肾上腺（HPA）轴的复发和变稳态适应增加有关。过量饮酒还与皮质边缘 HPA 功能紊乱有关，这可能导致酒精依赖和高复发率。我们的初步证据表明，酒精依赖小鼠高自愿饮酒率的关键调节剂是小电导钙激活钾（SK）通道。内侧前额叶皮层 (mPFC) 和伏核 (NAc) 中的 SK 通道调节 NMDA 受体依赖性钙流入、内在兴奋性和基础放电率。我们的初步研究结果表明，慢性间歇性乙醇 (CIE) 暴露或长期应激后，C57BL/6J 小鼠 mPFC 和 NAc 中 SK 通道表达显着降低。此外，显微注射研究表明，阻断 NAc 中 SK 通道的活性会增强对照小鼠的自愿消费，但不会增强酒精依赖小鼠的自愿消费。这些数据表明，CIE 后观察到的 SK 通道下调与 CIE 暴露小鼠的饮酒量增加密切相关。因此，该提议的总体假设是，CIE 通过增加控制饮酒的关键大脑区域中 NMDA 受体的增加和 SK 通道活性的减少来增加谷氨酸能突触的兴奋。这些研究将检验以下假设：1) 慢性乙醇暴露和压力会改变谷氨酸能突触，2) 转基因小鼠的不同饮酒模式与 SK 通道表达的改变有关，3) mPFC 和 NAc 中的 SK 通道调节饮酒的增加在 CIE 暴露的小鼠中。我们期望从这些研究中收集的数据将增进我们对涉及酒精寻求行为的关键大脑区域突触可塑性的理解，并将验证 SK 通道是治疗酒精依赖的重要新治疗靶点的假设。