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：酒精中毒家族史是饮酒问题发展的危险因素。调节酒精效应的积极奖励价和负面奖励价的因素可能会影响重复和 /或有问题使用的可能性，因此引起了人们的关注。酒精在大脑中具有多个目标，可以独立地促进其行为影响。对包括酒精，氯胺酮和苯二氮卓类药物的各种药理探针的研究表明，酗酒的家族史阳性（FHP）或阴性（FHN）的健康个体之间存在差异。据越来越多的临床前证据表明，脑大麻素受体（CB-1R）功能参与了酒精和酒精饮用行为的药理作用。大麻素和酒精激活相同的奖励途径。 CB-1R激动剂刺激，CB-1R拮抗剂抑制酒精自我给药和酒精的动机性能。与野生型小鼠相比，CB-1R基因敲除小鼠1）饮酒率和消耗的水平显着降低，2）饮酒行为的获取速度较慢，3）降低酒精敏感性，4）4）在核中，钝性酒精诱导的酒精诱导的多巴胺释放。最后，与避免饮酒的小鼠相比，酒精偏爱小鼠的CB-1R结合位点的水平明显较低，对CB-1R激动剂的亲和力更高。尽管有这些临床前数据，但该领域仍缺乏临床研究。 假设：具有酒精中毒家族史（FHP）的个体会表现出钝性的1）欣快感，2）感知和3）与没有酒精中毒家族史（FHN）的人相比，与？-9-四氢大麻酚（？9-THC）相比，响应了？-9-四氢大麻酚（？9-THC）。 方法：健康的FHN和FHP的数量相等（n = 18）将在一周内完成3个测试天，在此期间，他们将在20分钟内接受静脉注射的？9-THC（0、0.018和0.018和0.036 mg/kg），在双盲条件下随机，平衡的时尚。主要结果变量包括欣快的度量，感知改变和延迟召回。 初步结果：FHP个体（n = 4）表现出对？9-thc对欣快感，感知改变和相对于FHN对照的持续召回迟钝的反应。这些结果可能反映了FHP个体中CB-1R功能改变的间接证据。