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.

项目摘要 青少年发展期间的慢性应激增加了对许多人的敏感性 成年后的神经精神疾病，包括饮酒和类似焦虑的行为。社会隔离是 一个特别深刻的压力源，人类相关性的增加，尤其是在19日大流行期间 当数以百万计的青少年面临漫长的时期，与有限和间歇性的社交互动与 同龄人。内源性大麻素系统（ECS）与大脑发育至关重要，并调节突触 传输过程，包括杏仁核中央核（CEA）中央核的传输过程，这是压力和动画的枢纽 加工。越来越多的证据表明，青少年的社会隔离压力和饮酒 通过破坏EC并导致长期的突触神经适应来劫持发育的大脑 易于饮酒障碍（AUD），焦虑，侵略行为和社交互动缺陷。与众不同 成人酒精暴露，青少年饮酒的突触和行为影响通常不会恢复 随后的禁欲时期，表明经历社会隔离和饮酒期间 青少年有可能永久破坏大脑的发育轨迹。在这里，我将利用一个 间歇性的社会隔离压力的修改模型检查1）间歇性社会隔离对 雄性和雌性Wistar大鼠的青少年期间的酒精摄入量和偏好（PND28-56），2） 青少年社会隔离和饮酒对EC-的个人和协同后果 介导的机制有助于类似动画的行为和社交互动的长期影响。 此外，我将评估CEA中的ECS神经适应性，并验证EC作为潜在的药物靶标（AIM 1/k99）。我的假设是青少年隔离压力和饮酒会引起持久的改变 CEA中通过EC的不良适应功能（下调），GABA能和谷氨酸能信号传导（AIM 2/k99-r00）。最后，鉴于先前的工作以及我的初步数据表明操纵ECS 减少饮酒和类似焦虑症的行为，我将评估内源性大麻素的语气是否增加 （即2-ag）在青春期后的节制期间，通过阻止ECS酶促降解为 有效减少焦虑表型并防止成年后的饮酒缓解（AIM 3/R00）。 该提案的K99部分涉及使用分子和电生理方法进行广泛的训练 探究ECS系统的功能保护作用，以防止后来的饮酒和动画中的升级 - 喜欢行为。总的来说，这些实验将为青少年隔离的影响提供关键的见解 在两性的行为和突触传播上的压力和饮酒，并将验证 EC作为AUD和合并行为的可吸毒目标。我将接受的技术和概念培训 在此奖项期间，我将为继续这条研究线所需的多学科方法。 独立。