Stress and Ethanol Dependence: SK Channels and Glutamate

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）轴的复发和适应增加有关。过量饮酒也与皮质边缘-下丘脑功能紊乱有关，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活化钾（SK）通道。内侧前额叶皮层（mPFC）和伏隔核（NAc）中的SK通道调节NMDA受体依赖性钙内流、内在兴奋性和基础放电率。我们的初步研究结果表明，慢性间歇乙醇（CIE）暴露或长时间应激后，C57BL/6J小鼠mPFC和NAc中SK通道的表达显著降低。此外，显微注射研究表明，阻断NAc中SK通道的活性可以增强对照组小鼠的自愿消费，而不是酒精依赖小鼠。这些数据表明，CIE暴露后观察到的SK通道的下调与CIE暴露小鼠饮酒的增加密切相关。因此，该提议的总体假设是，CIE通过增加NMDA受体和减少控制饮酒的关键大脑区域的SK通道活性的结合，增加了谷氨酸突触的兴奋。这些研究将验证以下假设：1)慢性乙醇暴露和应激改变谷氨酸能突触；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CIE暴露小鼠的饮酒升级。我们期望从这些研究中收集的数据将促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。

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.