The Role of Endocannabinoids in Adulthood Alcohol Drinking After Adolescent Social Isolation

内源性大麻素在青少年社会隔离后成年饮酒中的作用

• 批准号: 10739510
• 负责人: Valentina Vozella
• 金额: $ 17.61万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739510
• 关键词: 2-arachidonylglycerol; Abstinence; Acute; Adolescence; Adolescent; Adult; Affect; Aggressive behavior; Alcohol consumption; Alcohols; Amygdaloid structure; Anxiety; Award; Behavior; Behavior Disorders; Behavioral; Brain; COVID-19 pandemic; Cell Nucleus; Chronic; Chronic stress; Coupled; Data; Development; Disease; Down-Regulation; Drug Targeting; Electrophysiology (science); Endocannabinoids; Female; Frequencies; Future; Glutamates; Grouping; Human; In Situ Hybridization; Individual; Intervention; Joints; Life; Lifestyle-related condition; Long-Term Effects; Longevity; MAGL inhibitor; Measures; Mediating; Modeling; Molecular; Monoacylglycerol Lipases; Phenotype; Physiological; Predisposition; Public Health; Rattus; Recording of previous events; Relapse; Research; Role; Sex Differences; Signal Transduction; Slice; Social Interaction; Social isolation; Stress; Stress and Coping; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Training; Vulnerable Populations; Water; Wistar Rats; Work; adolescent binge drinking; alcohol exposure; alcohol preferring rats; alcohol seeking behavior; alcohol use disorder; anxiety reduction; anxiety-like behavior; anxiety-related behavior; anxious; comorbidity; coping mechanism; drinking; drug candidate; drug reward; druggable target; endogenous cannabinoid system; experience; experimental study; gamma-Aminobutyric Acid; glutamatergic signaling; insight; interdisciplinary approach; lipidomics; male; neuroadaptation; neurobiological mechanism; neuropsychiatric disorder; neurotransmission; new therapeutic target; peer; pharmacologic; preference; prevent; reduced alcohol use; sex; social stress; social stressor; stressor; synaptic function; therapeutic target; tool; trait; transmission process; treatment effect; underage drinking

PROJECT SUMMARY Chronic stress during the developmental period of adolescence increases the susceptibility to many neuropsychiatric diseases in adulthood, including alcohol drinking and anxiety-like behaviors. Social isolation is a particularly profound stressor with increasing human relevance, especially during the COVID-19 pandemic, when millions of adolescents have faced prolonged periods with limited and intermittent social interactions with peers. The endocannabinoid system (ECs) is critically involved in brain development and modulates synaptic transmission processes, including those in the central nucleus of the amygdala (CeA), a hub of stress and anxiety processing. A growing body of evidence indicates that adolescent social isolation stress and alcohol drinking hijacks the developing brain by disrupting the ECs and resulting in long-lasting synaptic neuroadaptations that predispose to alcohol use disorder (AUD), anxiety, aggressive behaviors, and social interaction deficits. Unlike adult alcohol exposure, the synaptic and behavioral effects of adolescent binge drinking often do not recover following periods of abstinence, suggesting that experiencing social isolation and alcohol drinking during adolescence has the potential to permanently disrupt the brain’s developmental trajectory. Here, I will utilize a modified model of intermittent social isolation stress to examine 1) the effect of intermittent social isolation on alcohol intake and preference during adolescence (PND28-56) in male and female Wistar rats and 2) identify the individual and synergistic consequences of adolescent social isolation and alcohol drinking on the EC- mediated mechanisms contributing to the anxiety-like behaviors and social interactions long-term effects. Additionally, I will assess the ECs neuroadaptations in the CeA and validate ECs as a potential drug target (AIM 1/K99). My hypothesis is that adolescent isolation stress and alcohol drinking induce lasting alterations on GABAergic and glutamatergic signaling in the CeA via maladaptive functions (downregulation) of the ECs (AIM 2/K99-R00). Finally, given that previous work as well as my preliminary data suggest that manipulating the ECs reduces alcohol drinking and anxiety-like behaviors, I will assess whether increasing endocannabinoids’ tone (i.e., 2-AG) during the abstinence period post-adolescence, by blocking ECs enzymatic degradation, is efficacious in reducing the anxious phenotype and in preventing drinking relapse in adulthood (AIM 3/R00). The K99 portion of this proposal involves extensive training using molecular and electrophysiological approaches to probe the functional protective role of the ECs system against later escalations in alcohol drinking and anxiety- like behaviors. Collectively, these experiments will provide critical insights into the impact of adolescent isolation stress and alcohol drinking on the resulting behavior and synaptic transmission in both sexes and will validate the ECs as druggable target for AUD and comorbid behaviors. The technical and conceptual training I will receive during this award will equip me with the multidisciplinary approach needed to continue this research line independently.

项目概要 青春期发育期间的慢性压力会增加许多因素的易感性 成年后的神经精神疾病，包括饮酒和类似焦虑的行为，都是社交孤立的表现。 一种特别深刻的压力源，与人类的相关性越来越大，尤其是在 COVID-19 大流行期间， 当数以百万计的青少年长期面临有限且间歇性的社交互动时 内源性大麻素系统（EC）对于大脑发育和突触调节至关重要。 传输过程，包括杏仁核中央核 (CeA) 的传输过程，杏仁核是压力和焦虑的枢纽 越来越多的证据表明青少年的社会孤立压力和饮酒有关。 通过破坏内皮细胞并导致持久的突触神经适应来劫持大脑发育 容易出现酒精使用障碍 (AUD)、焦虑、攻击性行为和社交互动缺陷。 成人酒精暴露、青少年酗酒对突触和行为的影响通常不会恢复 禁欲期后，表明在禁欲期间经历社会孤立和饮酒 青春期有可能永久扰乱大脑的发育轨迹。 间歇性社交隔离压力的改进模型来检验 1) 间歇性社交隔离对 雄性和雌性 Wistar 大鼠青春期 (PND28-56) 的酒精摄入量和偏好以及 2) 确定 青少年社会孤立和饮酒对 EC-的个体和协同后果 导致焦虑样行为和社会互动长期影响的介导机制。 此外，我将评估 CeA 中的 ECs 神经适应并验证 ECs 作为潜在的药物靶点（AIM 1/K99）我的假设是青少年孤立压力和饮酒会导致持久的改变。 通过 EC 的适应不良功能（下调），CeA 中的 GABA 能和谷氨酸能信号传导 (AIM 2/K99-R00）最后，鉴于之前的工作以及我的初步数据表明操纵 EC 减少饮酒和类似焦虑的行为，我将评估是否增加内源性大麻素的语气 （即 2-AG）在青春期后禁欲期间，通过阻断 ECs 酶促降解， 有效减少焦虑表型并防止成年后酗酒复发（AIM 3/R00）。 该提案的 K99 部分涉及使用分子和电生理学方法进行广泛的培训 探讨 ECs 系统对以后饮酒和焦虑升级的功能保护作用 总的来说，这些实验将为青少年孤立的影响提供重要的见解。 压力和饮酒对两性行为和突触传递的影响，并将验证 EC 作为 AUD 和共病行为的药物靶点 我将接受的技术和概念培训。 在这个奖项期间，我将掌握继续这一研究方向所需的多学科方法 独立。