Cannabinoid Receptor Function in Alcoholism: Effects of D-9-THC

大麻素受体在酒精中毒中的功能：D-9-THC 的作用

• 批准号: 7257682
• 负责人: DEEPAK Cyril D'SOUZA
• 金额: $ 15.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257682
• 关键词: Affinity; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; Area; Auditory; Behavioral; Benzodiazepines; Binding Sites; Brain; Cannabinoids; Clinical Research; Condition; Consumption; Data; Dependence; Development; Dopamine; Dose; Double-Blind Method; Environmental Risk Factor; Ethanol; Euphoria; Exhibits; Family history of; GABA-A Receptor; Genetic; Glutamates; Impairment; Individual; Individual Differences; Intravenous; Ketamine; Knock-out; Knockout Mice; Learning; Measures; Mediating; Methods; Minority; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nucleus Accumbens; Numbers; Outcome; Pathway interactions; Property; Randomized; Rate; Relative (related person); Rewards; Risk Factors; Sampling; Self Administration; Symptoms; System; Testing; Tetrahydrocannabinol; Time; Title; Verbal Learning; Visual Analogue Pain Scale; Week; Wild Type Mouse; alcohol avoiding mice; alcohol effect; alcohol measurement; alcohol preferring mice; alcohol related problem; alcohol sensitivity; cannabinoid receptor; day; drinking behavior; interest; pre-clinical; preference; receptor function; receptor sensitivity; response

DESCRIPTION (provided by applicant): Background: A family history of alcoholism is a risk factor for the development of alcohol problems. Factors that modulate the positive and negative reward valence of alcohol effects may influence the likelihood of repeated and or problematic use, and are therefore of interest. Alcohol has multiple targets in the brain that independently contribute to its behavioral effects. Studies with various pharmacological probes including alcohol, ketamine and benzodiazepines suggest differences between healthy individuals with a family history positive (FHP) or negative (FHN) for alcoholism. There is growing preclinical evidence suggesting involvement of brain cannabinoid receptor (CB-1R) function in the pharmacological actions of alcohol and in alcohol-drinking behaviors. Cannabinoids and alcohol activate the same reward pathways. CB-1R agonists stimulate while CB-1R antagonists suppress, alcohol self-administration and the motivational properties of alcohol. Comparison to wild type mice, CB-1R knockout mice show 1) significantly lower levels of alcohol preference and consumption, 2) slower rate of acquisition of alcohol drinking behavior, 3) lower alcohol sensitivity, and 4) blunted alcohol-induced dopamine release in the nucleus accumbens. Finally, alcohol preferring mice have a significantly lower level of CB-1R binding sites and higher affinity for CB-1R agonist than alcohol-avoiding mice. Despite these preclinical data, there is a paucity of clinical research in this area. Hypotheses: Individuals with a family history of alcoholism (FHP) will exhibit blunted 1) euphoric, 2) perceptual and 3) amnestic effects in response to ?-9-tetrahydrocannabinol (?9-THC) administration compared to individuals without a family history of alcoholism (FHN). Methods: An equal number (n=18) of healthy FHN and FHP will complete 3 test days separated by a week during which they will receive intravenous ?9-THC (0, 0.018 and 0.036 mg/kg) over 20 minutes in randomized, counterbalanced fashion under double-blind conditions. Primary outcome variables include measures of euphoria, perceptual alterations and delayed recall. Preliminary Results: FHP individuals (n=4) showed blunted responses to the effects of ?9-THC on euphoria, perceptual alterations and delayed recall relative to FHN controls. These results may reflect indirect evidence of altered CB-1R function in FHP individuals.

描述（由申请人提供）： 背景：酗酒家族史是出现酒精问题的危险因素。调节酒精效应的正向和负向奖励效价的因素可能会影响重复和/或有问题的使用的可能性，因此令人感兴趣。酒精在大脑中有多个目标，这些目标独立地影响其行为效果。对包括酒精、氯胺酮和苯二氮卓类药物在内的各种药理学探针的研究表明，具有酗酒家族史阳性（FHP）或阴性（FHN）家族史的健康个体之间存在差异。越来越多的临床前证据表明大脑大麻素受体（CB-1R）功能参与酒精的药理作用和饮酒行为。大麻素和酒精激活相同的奖励途径。 CB-1R 激动剂刺激酒精自我管理和酒精的激励特性，而 CB-1R 拮抗剂则抑制酒精的激励特性。与野生型小鼠相比，CB-1R 基因敲除小鼠表现出 1）酒精偏好和消费水平显着降低，2）饮酒行为的获得速度较慢，3）酒精敏感性较低，4）酒精诱导的多巴胺释放减弱伏隔核。最后，与避免饮酒的小鼠相比，偏好饮酒的小鼠具有显着较低水平的 CB-1R 结合位点和对 CB-1R 激动剂的更高亲和力。尽管有这些临床前数据，但该领域的临床研究仍然很少。 假设：与没有酗酒家族史的个体相比，有酗酒家族史 (FHP) 的个体对 ?-9-四氢大麻酚 (?9-THC) 给药的反应会表现出迟钝的 1) 欣快感、2) 知觉效应和 3) 遗忘效应。酗酒（FHN）。 方法：同等数量 (n = 18) 的健康 FHN 和 FHP 将完成 3 个测试日，间隔一周，在此期间，他们将在 20 分钟内随机接受静脉注射 ?9-THC（0、0.018 和 0.036 mg/kg），双盲条件下的平衡时尚。主要结果变量包括欣快感、知觉改变和延迟回忆的测量。 初步结果：与 FHN 对照相比，FHP 个体 (n=4) 对 9-THC 对欣快感、知觉改变和延迟回忆的影响反应迟钝。这些结果可能反映 FHP 个体中 CB-1R 功能改变的间接证据。