Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling

酒精暴露可逆转恐惧调节引起的内源性大麻素信号变化

• 批准号: 10310410
• 负责人: Muhammad A. Farooq
• 金额: $ 3.79万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310410
• 关键词: 2-arachidonylglycerol; Agonist; Alcohols; Animal Model; Anxiety Disorders; Area; Arousal; Attenuated; Behavioral; Binding; Biological Assay; Brain; Brain region; CNR1 gene; CXCL2 gene; Cannabis; Cerebellum; Cerebral cortex; Chronic; Clinical; DNA; Development; Disease; Electrophysiology (science); Emotional; Endocannabinoids; Environment; Enzymes; Exhibits; Extinction (Psychology); Fright; Future; Genes; Genetic Transcription; Glycerol; Growth and Development function; Health Sciences; Impairment; Individual; Interneurons; Lead; Learning; Lipids; Mediating; Medicine; Memory; Mental disorders; Mentors; Modeling; Molecular; Monoacylglycerol Lipases; Moods; Motor; Mus; Neuroglia; Neuromodulator; Neurons; Neurosciences; PPAR alpha; Pathological anxiety; Pathology; Patients; Pharmacology; Physicians; Physiological Processes; Post-Traumatic Stress Disorders; Preparation; Procedures; Process; Promoter Regions; Research Infrastructure; Rewards; Role; Scientist; Stress; Structure; Structure of molecular layer of cerebellar cortex; Symptoms; Synaptic Transmission; Technology; Testing; Training; Up-Regulation; addiction; alcohol comorbidity; alcohol exposure; alcohol reinforcement; alcohol research; alcohol use disorder; cannabinoid receptor; career; combat veteran; comorbidity; conditioned fear; designer receptors exclusively activated by designer drugs; endocannabinoid signaling; enzyme activity; extracellular; fear memory; gamma-Aminobutyric Acid; granule cell; insight; marijuana use; memory consolidation; memory process; memory retention; negative mood; novel therapeutics; prevent; reduce symptoms; symptom cluster; transcription factor; vapor

Alcohol exposure reverses fear conditioning-induced change in endocannabinoid signaling Post-traumatic stress disorder (PTSD) is a severe anxiety disorder characterized by a cluster of symptoms including intrusive memories and hyper-arousal and reactivity. Maladaptive fear learning is one of the possible mechanisms underlying disease pathology. Endocannabinoids, lipid neuromodulators, control several physiological processes such as memory and mood are found to be altered in PTSD patients. PTSD patients exhibit lower circulating endocannabinoids and increased level of cannabinoid receptor 1. Hence, cannabinoid receptor agonists have been used to alleviate symptoms of PTSD. Nearly half of patients suffering from PTSD meet the criteria for alcohol use disorder (AUD). Alcohol exposure has been shown to increase endocannabinoids in several areas of the brain. This raise the possibility that decrease in endocannabinoid signaling is not only involved in PTSD, but may also cause alcohol reinforcement. Mounting evidence has implicated cerebellum in fear learning, emotional learning, and reward. My preliminary results show that the fear conditioning increases monoacyl glycerol (MAGL) activity increasing endocannabinoid degradation in the cerebellum. In contrast, chronic alcohol exposure decreases MAGL activity. Our central hypothesis is that fear conditioning elevates MAGL activity and reduces eCB tone, which promotes retention of fear memories, while subsequent alcohol exposure reverses these changes in the cerebellum. Aim 1 investigate the mechanisms of increased MAGL activity. Aim 2 will study the mechanisms by which alcohol exposure reduces MAGL activity using depolarization suppression of excitation and enzyme activity assay. Aim 2 will also investigate the effect of chronic alcohol exposure on fear memory retention. This study will provide mechanistic insight about PTSD comorbid AUD, which may lead to development of new therapeutics for this comorbidity.

酒精暴露会逆转恐惧调节引起的内源性大麻素信号的变化 创伤后应激障碍（PTSD）是一种严重的焦虑症，其特征是一群症状 包括侵入性记忆以及超声和反应性。适应不良的恐惧学习是可能的 疾病病理学的机制。内源性大麻素，脂质神经调节剂，控制几个 PTSD患者发现了记忆和情绪等生理过程，例如记忆和情绪。 PTSD患者 表现出较低的循环内源性大麻素和大麻素受体的水平升高1。因此，大麻素 受体激动剂已被用来减轻PTSD的症状。近一半患有PTSD的患者 符合酒精使用障碍标准（AUD）。酒精暴露已被证明增加 大脑多个区域的内源性大麻素。这增加了内源性大麻素减少的可能性 信号不仅参与PTSD，而且还可能引起酒精加强。越来越多的证据有 在恐惧学习，情感学习和回报中暗示了小脑。我的初步结果表明恐惧 调节增加单酰基甘油（MAGL）活性增加了内源性大麻素的降解 小脑。相反，慢性酒精暴露会降低MAGL活性。我们的中心假设是恐惧 调理可以提升MAGL活动并减少欧洲央行的音调，从而促进恐惧记忆的保留，而 随后的酒精暴露会逆转小脑中的这些变化。 AIM 1调查机制 增加MAGL活性。 AIM 2将研究酒精暴露减少MAGL活性的机制 使用抑制激发和酶活性测定法。 AIM 2还将调查效果 长期暴露于恐惧记忆力。这项研究将提供有关PTSD的机械洞察力 合并的AUD，这可能会导致这种合并症的新疗法。