PHARMACOLOGICAL ANTAGONISM AND GENETIC MANIPULATION OF CANNABINOID CB1 RECEPTORS IN THE AMYGDALA TO REDUCE PROTRACTED ETHANOL CONSUMPTION

杏仁核中大麻素 CB1 受体的药理拮抗和基因操作可减少长期乙醇消耗

• 批准号: 10159728
• 负责人: Russell Scott Dulman
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159728
• 关键词: Acetylation; Agonist; Alcohol consumption; Alcohols; Amygdaloid structure; Animals; Behavior; Behavioral; Biochemical; Brain; CNR1 gene; Cannabinoids; Cell Nucleus; Chronic; Complex; Consumption; Control Groups; Data; Endocannabinoids; Enzymes; Epigenetic Process; Ethanol; Female; Functional disorder; Gene Expression; Genetic; Health; Heroin; Hour; In Situ Hybridization; Infusion procedures; Injections; KDM1A gene; Location; Measures; Mediating; Mental disorders; Messenger RNA; Metabolic; Methylation; Modification; Molecular; Mus; Neurobiology; Nicotine; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; RNA; Recording of previous events; Regulation; Rodent; Self Administration; Signal Transduction; Small Interfering RNA; System; Testing; Translating; Water; addiction; alcohol abuse therapy; alcohol effect; alcohol exposure; alcohol use disorder; base; cannabinoid receptor; cannabinoid receptor antagonist; chronic alcohol ingestion; density; drinking; drinking behavior; endocannabinoid signaling; endogenous cannabinoid system; epigenetic regulation; experimental study; genetic manipulation; histone acetyltransferase; histone modification; improved; innovation; intraperitoneal; knock-down; male; negative affect; novel; pre-clinical; promoter; receptor; rimonabant; sex

Project Summary/Abstract Alcohol Use Disorder (AUD) is a widespread problem with significant health and societal consequences and a need for improved treatments. The endogenous cannabinoid system is a promising target for new AUD pharmacotherapy. Prolonged ethanol consumption leads to molecular and epigenetic changes in the amygdala underlying the negative affective state in addiction. The amygdala has a high density of cannabinoid CB1 receptors. While cannabinoid antagonists reduce ethanol drinking, their ability to alter molecular and epigenetic changes in the amygdala remains unexplored. Furthermore, neutral cannabinoid receptor antagonists possess less psychiatric liabilities than older inverse agonists such as rimonabant. This project exploring cannabinoid receptor manipulations will provide evidence for a novel AUD pharmacotherapy and characterize the epigenetic regulation of the endocannabinoid system in drinking behaviors. Despite indications neutral cannabinoid receptor antagonism reduces drug and ethanol consumption, it is less clear how chronic ethanol drinking epigenetically impacts the endocannabinoid system or how CB1 receptors in specific addiction-related brain circuits such as the extended amygdala regulate drinking behaviors. This proposal is based on the hypothesis that modulation of the CB1 receptor system can reduce escalated ethanol drinking and reverse alcohol-induced changes in gene expression and histone modifications in the amygdala. We will test this hypothesis by assessing AM4113 effects on drinking behavior and biochemical changes in amygdalar endocannabinoid system gene expression and global and specific Cnr1 (CB1 mRNA) histone modifications following intermittent-access 20% ethanol drinking. We will further test the effect of Cnr1 knockdown within the central and basolateral nuclei of the amygdala on protracted drinking behavior to specifically localize sub-regions of the amygdala as sufficient for these same downstream behavioral and biochemical effects. Overall, these experiments will further the understanding of the endocannabinoid system and its epigenetic regulation during protracted ethanol drinking while providing key preclinical data for translating endocannabinoid-targeted treatments for AUD.

项目总结/摘要 酒精使用障碍（AUD）是一个广泛存在的问题， 后果和改善治疗的需要。内源性大麻素系统是一种 新AUD药物治疗的有前途的目标。长期的乙醇消耗导致 杏仁核中的分子和表观遗传变化是负性情感状态的基础， 成瘾杏仁核有高密度的大麻素CB 1受体。虽然大麻素 拮抗剂减少乙醇饮用，它们改变细胞中分子和表观遗传变化的能力， 杏仁核尚未被研究。此外，中性大麻素受体拮抗剂具有 比利莫那班等老的反向激动剂更少的精神负担。该项目探索 大麻素受体操纵将为新的AUD药物疗法提供证据， 表征饮酒行为中内源性大麻素系统的表观遗传调节。 尽管有迹象表明，中性大麻素受体拮抗剂减少了药物和乙醇 消费，尚不清楚慢性乙醇饮用如何影响表观遗传 内源性大麻素系统或CB 1受体如何在特定的成瘾相关的大脑回路， 延伸的杏仁核调节饮酒行为。这一提议是基于这样一种假设： CB 1受体系统的调节可以减少酒精饮用量的增加， 逆转酒精诱导的基因表达和组蛋白修饰的变化， 杏仁核我们将通过评估AM4113对饮酒行为的影响来验证这一假设， 杏仁核内源性大麻素系统基因表达的生化变化以及 20%乙醇处理后特异性Cnr 1（CB 1 mRNA）组蛋白修饰 喝酒我们将进一步测试Cnr 1敲低在中央和基底外侧核中的作用。 杏仁核的长期饮酒行为，以具体定位的子区域， 杏仁核足以产生这些下游行为和生化效应。总的来说， 这些实验将进一步了解内源性大麻素系统及其 在长期乙醇饮用过程中的表观遗传调控，同时提供关键的临床前数据， 翻译内源性大麻素靶向治疗AUD。