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.

项目摘要/摘要 酒精使用障碍（AUD）是健康和社会的普遍问题 后果和需要改善治疗方法。内源性大麻素系统是 新的AUD药物疗法的有希望的目标。长时间的乙醇消耗导致 杏仁核的分子和表观遗传变化，其背后的阴性情感状态 瘾。杏仁核具有高密度的大麻素CB1受体。而大麻素 拮抗剂减少乙醇饮用，改变分子和表观遗传变化的能力 杏仁核仍然未开发。此外，中性大麻素受体拮抗剂拥有 与诸如Rimonabant等较老的反向激动剂相比，精神病责任少。这个项目探索 大麻素受体操纵将为新型AUD药物治疗提供证据 表征内源性大麻素系统在饮酒行为中的表观遗传调节。 尽管有迹象中性大麻素受体拮抗作用降低了药物和乙醇 消费量，尚不清楚慢性乙醇在表观上如何影响 内源性大麻素系统或特定成瘾相关脑电路中的CB1受体（例如 扩展的杏仁核调节饮酒行为。该提议基于假设 CB1受体系统的调节可以减少升级的乙醇饮用和 反向酒精诱导的基因表达变化和组蛋白修饰 杏仁核。我们将通过评估AM4113对饮酒行为的影响和 杏仁核内源性大麻素系统基因表达和全局的生化变化 间歇性访问20％乙醇后的特定CNR1（CB1 mRNA）组蛋白修饰 喝。我们将进一步测试中央和基底外侧核内CNR1敲低的效果 杏仁核关于旷日持久的饮酒行为，专门将 杏仁核足以满足相同的下游行为和生化作用。全面的， 这些实验将进一步了解内源性大麻素系统及其ITS系统 长期乙醇饮用过程中的表观遗传调节，同时提供关键的临床前数据 翻译aud的内源性大麻素靶向治疗方法。