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.

青少年和青年时期开始的暴饮暴食或过量饮酒是成瘾的一个强烈危险因素 这个弱势年龄组的发育和其他心理健康问题。有效的治疗策略 应对日益流行的青少年酗酒和酗酒问题需要更多的科学依据 了解生命早期酗酒对一生中大脑功能的长期影响。 我们之前发现内源性 sigma-1 受体在调节海马功能中的新作用 通过对成熟青少年大脑中突触长期增强过程的影响。项目 本文提出的方法将进一步增进我们对 sigma-1 受体在认知或认知功能中的功能的理解。 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) 青春期早期大鼠长期酗酒会上调 sigma-1 受体蛋白 表达，触发记忆所在海马体突触可塑性信号通路的开关 初步形成并排序； (2) 青春期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 海马体； (3) 酒精 x sigma-1 受体相互作用引起的神经适应性变化反映 细胞内信号级联的激活干扰海马的正常信号处理 成熟的青少年大脑。将通过结合电生理学技术（即， 脑切片记录和体内脑电图分析）与生化方法（蛋白质印迹分析）使用 通过慢性间歇性接触诱发暴饮暴食和依赖性的青少年大鼠模型 乙醇蒸气。测试将在不同长度的戒酒后进行，以确定长期戒酒范围 在青少年到年轻人的发展过程中，不同时期暴饮暴食的后果。中央 给予 sigma-1 受体选择性激动剂/拮抗剂将有助于证实 sigma-1 受体 成熟青少年大脑中酒精作用的功能相关目标，提供了重要的见解 与酒精滥用相关的持续性认知病理的分子机制始于生命早期。