Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

在青少年和年轻人的早期开始的酗酒或过度饮酒是成瘾的一个很大的危险因素 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的需求更科学 了解早期酒精滥用对一生中大脑功能的长期影响。 我们以前发现了内源性sigma-1受体在调节海马功能中的新作用 通过对成熟的青少年大脑中突触长时程增强过程的影响。项目 本文中提出的将进一步推进我们对认知或神经系统中σ-1受体功能的理解。 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）青春期早期大鼠的慢性酒精滥用上调sigma-1受体蛋白 表达，触发海马体中突触可塑性信号通路的开关，记忆是 最初形成和分类;（2）青少年早期酒精滥用结果后的sigma-1受体诱导 参与经验诱导的神经可塑性的选择电压依赖性离子通道的活性改变， 海马;（3）酒精x sigma-1受体相互作用引起的神经适应性变化反映了 激活细胞内信号级联，干扰海马正常信号处理， 成熟的青少年大脑将通过结合电生理技术（即， 脑切片记录和体内EEG分析）与生化方法（Western印迹分析），使用 通过慢性间歇性暴露的青少年大鼠暴食样滥用和依赖诱导模型 乙醇蒸气。测试将发生后，不同长度的酒精戒断，以确定长期 在成年人到青年人的发育过程中，在不同的时间，暴饮暴食的后果。中央 施用σ-1受体选择性激动剂/拮抗剂将有助于证实σ-1受体作为 功能相关的目标酒精行动在成熟的青少年大脑，提供关键的见解， 与酗酒有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.