CANNABINOIDERGIC CONTROL OF ALCOHOL RELATED BEHAVIORS

大麻素对酒精相关行为的控制

• 批准号: 7227292
• 负责人: BASALINGAPPA Lingappa HUNGUND
• 金额: $ 8.12万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227292
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; anandamide; behavior test; behavioral /social science research tag; brain mapping; cannabinoid receptor; cannabinoids; dopamine; ethanol; gas chromatography mass spectrometry; gene expression; gene targeting; genetic regulation; genetically modified animals; genotype; laboratory mouse; male; microdialysis; nucleus accumbens; pharmacokinetics; phenotype; preference; receptor binding; substance abuse related behavior; tissue /cell preparation

Although the exact mechanism of interaction of ethanol (EtOH) with its neuronal targets is not yet understood, there is evidence that EtOH interacts with specific neuronal membrane receptor proteins to alter their normal function. Examples of receptors for which evidence supports a direct interaction with EtOH include; GABA-A, glutamate and several serotonin receptors. Newly developed methods for targeted alteration of gene function offer the possibility of establishing a cause and effect relationship between an action of EtOH on a molecular target and an EtOH-induced behavioral change. The current proposal focuses on the function of one such protein hitherto unexplored, namely cannabinoid (CB1) receptor in EtOH drinking and EtOH-related behaviors. Studies have indicated that there are genetic differences in the density and affinity of CB1 receptors in the brains of two strains of mouse found to differ in their preferences for EtOH. It has been demonstrated that administration of CB1 receptor antagonists reduced EtOH intake in EtOH-preferring mice. Based on these findings it is hypothesized that the genetically based differences in the brain levels and distribution of endocannabinoid ANA and CB1 receptors influence EtOH drinking behavior, and genetic manipulation through disruption of the gene for CB1 receptor protein will modulate the CB1-ergic system and the behavioral effects of EtOH. The Specific Aims are: (1) to generate CBI receptor knockout mice with two different genetic backgrounds (2) study the effect of gene disruption on (2) the levels and distribution of anandamide and its receptor (CB1) in various brain regions, EtOH drinking, and other EtOH-related behaviors, (4) the effects of CB1 receptor agonist and antagonist on EtOH drinking and other EtOH-related behaviors, and (5) to investigate the dopamine release in nucleus accumbens. The long-term goal is to develop medication for treatment of problems associated with alcohol abuse and alcoholism, which would be comparable to medical use of marijuana. Studies with synthetic analogues of ANA or other agonists and antagonists will open up new avenues in alcohol research.

尽管乙醇 (EtOH) 与其神经元靶标相互作用的确切机制尚不清楚，但有证据表明 EtOH 与特定的神经元膜受体蛋白相互作用以改变其正常功能。 有证据支持与 EtOH 直接相互作用的受体的例子包括： GABA-A、谷氨酸和几种血清素受体。新开发的基因功能定向改变方法提供了在乙醇对分子靶标的作用与乙醇诱导的行为变化之间建立因果关系的可能性。 目前的提案重点关注一种迄今尚未探索的蛋白质的功能，即大麻素 (CB1) 受体在乙醇饮酒和乙醇相关行为中的功能。 研究表明，两种小鼠品系的大脑中 CB1 受体的密度和亲和力存在遗传差异，这两种小鼠对乙醇的偏好不同。 已经证明，给予 CB1 受体拮抗剂可以减少偏好 EtOH 的小鼠的 EtOH 摄入量。 基于这些发现，推测内源性大麻素 ANA 和 CB1 受体的大脑水平和分布的遗传差异影响乙醇饮酒行为，并且通过破坏 CB1 受体蛋白基因进行基因操作将调节 CB1 能系统和乙醇的行为影响。 具体目标是：(1) 生成具有两种不同遗传背景的 CBI 受体敲除小鼠 (2) 研究基因破坏对 (2) 不同脑区中 anandamide 及其受体 (CB1) 的水平和分布、EtOH 的影响饮酒和其他EtOH相关行为，（4）CB1受体激动剂和拮抗剂对EtOH饮酒和其他EtOH相关行为的影响，以及（5）研究细胞核中多巴胺的释放伏隔核。 长期目标是开发药物来治疗与酗酒和酗酒相关的问题，这与大麻的医疗用途相当。 ANA 的合成类似物或其他激动剂和拮抗剂的研究将为酒精研究开辟新途径。

项目成果

Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors.

内源性大麻素和大麻素 CB1 受体在酒精相关行为中的作用。

• 发表时间: 2004-10
• 作者: Hungund, Basalingappa L;Basavarajappa, Balapal S
• 通讯作者: Basavarajappa, Balapal S

Common Factors Underlying Diverse Responses in Alcohol Use Disorder.

酒精使用障碍的不同反应背后的常见因素。

• 发表时间: 2021
• 作者: Chebolu, Esha;Schwandt, Melanie L;Ramchandani, Vijay A;Stangl, Bethany L;George, David T;Horneffer, Yvonne;Vinson, Tonette;Vogt, Emily L;Manor, Brandon A;Diazgranados, Nancy;Goldman, David
• 通讯作者: Goldman, David

Pharmacological manipulation of CB1 receptor function alters development of tolerance to alcohol.

CB1受体功能的药理学操作改变了对酒精的耐受性的发展。

• 发表时间: 2006-01
• 作者: Nowak, Karen L;Vinod, K Yaragudri;Hungund, Basalingappa L
• 通讯作者: Hungund, Basalingappa L

Investigation on the relationship between cannabinoid CB1 and opioid receptors in gastrointestinal motility in mice.

大麻素CB1与阿片受体对小鼠胃肠动力关系的研究。

• 发表时间: 2006-08
• 影响因子: 7.3
• 作者: Carai, Mauro A M;Colombo, Giancarlo;Gessa, Gian Luigi;Yalamanchili, Ratnakumar;Basavarajappa, Balapal S;Basavarajppa, Balapal S;Hungund, Basalingappa L
• 通讯作者: Hungund, Basalingappa L

Role of the endocannabinoid system in the development of tolerance to alcohol.

内源性大麻素系统在酒精耐受性发展中的作用。

• 发表时间: 2005-01
• 作者: Basavarajappa, Balapal S;Hungund, Basalingappa L
• 通讯作者: Hungund, Basalingappa L