Molecular Mechanisms of Alcohol Actions in the Adolescent Brain

青少年大脑中酒精作用的分子机制

• 批准号: 8733358
• 负责人: JILLA SABETI
• 金额: $ 18.09万
• 依托单位: WESTERN NEW ENGLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733358
• 关键词: Molecular; Mechanisms; Alcohol; Actions; Adolescent

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.

在青少年和成年年轻人的早期开始的暴饮暴食或过多的饮酒是成瘾的强大风险因素 在这个脆弱的年龄组中的发展和其他心理健康问题。有效的治疗策略 反对青春期酗酒和酒精中毒的流行病的日益增长的科学要求 了解早期酗酒对整个生命的脑功能的长期影响。 我们以前确定了内源性Sigma-1受体在调节海马功能中的新作用 通过对成熟青春期大脑突触长期增强过程的影响。项目 本文提出的将进一步提高我们对认知或认知或 青春期早期酗酒的记忆方面。该项目的具体目的是测试 假设：（1）早期大鼠的慢性酒精滥用在上调Sigma-1受体蛋白 表达，在海马中触发突触可塑性信号通路的开关 最初形成和分类； （2）早期青春期酗酒结果后的Sigma-1受体诱导 在参与经验诱导的神经塑性中的某些电压依赖性离子通道的活性改变中 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 细胞内信号传导的激活级联反应干扰正常信号处理的海马 成熟的青春期大脑。假设将通过结合电生理技术来检验（即 使用生化方法（Western blot分析）的脑切片记录和体内EEG分析） 通过慢性间歇性暴露于狂饮样滥用和依赖性诱导的青少年大鼠模型 乙醇蒸气。在戒酒长度变化后，将进行测试以确定远距离 在青少年到年轻人成人发展期间不同时间暴饮暴食的后果。中央 施用Sigma-1受体选择性激动剂/拮抗剂将有助于证实Sigma-1受体作为 在成熟的青少年大脑中酒精作用的功能相关目标，为 与酗酒有关的持续认知病理的分子机制是在生命早期引发的。