Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

在青少年和青年时期就开始酗酒或酗酒是成瘾的强烈风险因素 在这一弱势年龄组中的发展和其他心理健康问题。有效的治疗策略 针对日益流行的青少年酗酒和酗酒要求更多的科学 了解早年酗酒对终生大脑功能的长期影响。 我们先前发现了内源性Sigma-1受体在调节海马区功能中的新作用 通过对成熟青春期大脑中突触长时程增强过程的影响。项目 本文的提出将进一步促进我们对Sigma-1受体在认知或治疗中的作用的理解。 青春期早期酗酒的记忆方面。该项目的具体目标是测试 假设：(1)青春期早期大鼠慢性酒精滥用上调Sigma-1受体蛋白 表达，触发记忆所在的海马区突触可塑性信号通路的切换 最初形成和分类；(2)青少年早期酗酒后Sigma-1受体的诱导 在参与经验诱导的神经可塑性的选择性电压依赖离子通道的活性改变中 (3)酒精与西格玛-1受体相互作用引起的神经适应性变化反映了 细胞内信号级联激活干扰大鼠海马区正常信号处理 成熟的青春期大脑。假说将通过结合电生理技术(即， 脑切片记录和活体脑电分析)和生物化学方法(Western印迹分析)使用 一种慢性间歇性暴露于青春期大鼠的暴饮样虐待和依赖诱导模型 乙醇蒸气。测试将在不同的戒酒时间后进行，以确定长距离 在青春期到青壮年发育的不同时期暴饮暴食的后果。中环 给予Sigma-1受体选择性激动剂/拮抗剂将有助于将Sigma-1受体证实为 在成熟的青少年大脑中酒精行为的功能相关靶点，为 与酒精滥用相关的持续性认知病理的分子机制在生命早期就开始了。

Binge or excessive drinking initiated early in teenage and young adult life is a strong risk factor for addiction development and other mental health problems in this vulnerable age-group. Effective treatment strategies against the growing epidemic of adolescent alcohol abuse and alcoholism demand greater scientific understanding of the long-term impact that early-life alcohol abuse wields on brain function throughout life. We identified previously a novel role for endogenous sigma-1 receptors in modulating hippocampal function through effects on synaptic long-term potentiation processes in the maturing adolescent brain. Projects proposed herein will further advance our understanding of sigma-1 receptor function in the cognitive or memory aspects of alcohol abuse in early adolescence. Specific Aims of the project are to test the hypotheses that: (1) chronic alcohol abuse in early-adolescent rats upregulates sigma-1 receptor protein expression, triggering a switch in synaptic plasticity signaling pathways in hippocampus where memories are initially formed and sorted; (2) sigma-1 receptors induction following early-adolescent alcohol abuse results in altered activity of select voltage-dependent ion channels involved in experience-induced neuroplasticity in hippocampus; (3) neuroadaptive changes arising from alcohol x sigma-1 receptor interactions reflect activation of intracellular signaling cascades that interfere with normal signal processing in hippocampus of the maturing adolescent brain. Hypotheses will be tested by combining electrophysiological techniques (i.e., brain slice recordings and in vivo EEG analyses) with biochemical approaches (Western blot analyses) using an adolescent rat model of binge-like abuse and dependence induction via chronic intermittent exposure to ethanol vapors. Testing will occur after varying lengths of alcohol abstinence to determine the long-range consequences of binge exposure at different times during adolescent-to-young adult development. Central administration of sigma-1 receptor selective agonists/antagonists will help substantiate sigma-1 receptors as functionally relevant targets of alcohol actions in the maturing adolescent brain, providing critical insights into the molecular mechanisms for persistent cognitive pathologies related to alcohol abuse initiated early in life.