5HT1B Receptor in Antisocial Alcoholics

说明： 大量临床和临床前研究表明， 酒精使用障碍和糖尿病患者5-羟色胺能神经传递均发生改变 在具有高度攻击性和冲动的个人中。几个 实验室已经表明，小鼠在饲养过程中缺乏编码 5-羟色胺5-HT1B受体显示攻击性行为水平升高， 更多的意志性饮酒，以及更大的自我管理 可卡因。这些结果清楚地表明这类5-羟色胺受体在 既有哺乳动物的攻击性，也有酗酒等吸毒行为。一致 通过在动物模型中的观察，已经证实了这种联系。 人类5-HT1B受体基因多态性与反社会性的关系 各种形式的酒精中毒。 这项拟议的探索性研究将扩展这些临床前和人类 研究5-HT1B的功能反应性 受体，使用Sumtriptan挑战范式，以及测量的基因 在一个研究人群中，编码这种受体的基因座的可变性 有反社会人格障碍和无反社会人格障碍的酒精依赖者。一个 非酒精、非反社会个体的对照组，他们是匹配的 关于年龄、性别、种族和美国人口普查区域的先驱也将 学习。后一组代表不受 酒精依赖和社会反常，尽管社会环境相似 曝光。 我们相信这种方法是创新的和启发式的，因为它直接 解决了基因的生理分支这一紧迫的问题 表情。如果5-羟色胺5-HT1b受体系统被发现广泛 对反社会性的代际传播和 药物滥用，结果将把这个系统确定为显著的目标 用于未来的遗传和精神药理学研究。一点也不少 重要的是，精神药理药剂有可能- 该受体的特异性程度(例如“Triptans”，如Sumtriptan) 可以作为反社会障碍的潜在治疗药物 与药物滥用有关。

DESCRIPTION: A host of clinical and pre-clinical studies have demonstrated that serotonergic neurotransmission is altered both in Alcohol Use Disorders and among individuals with heightened aggression and impulsivity. Several laboratories have shown that mice bred to be lacking in the gene encoding the serotonin 5-HT1B receptor display heightened levels of aggressive behavior, increased volitional alcohol consumption, and greater self-administration of cocaine. These results clearly implicate this class of serotonin receptor in both mammalian aggression and alcohol and other drug use behavior. Consistent with this observation in the animal model, linkage has been demonstrated between polymorphisms of the gene for the human 5-HT1B receptor and antisocial forms of alcoholism. This proposed exploratory study will extend these pre-clinical and human studies by investigating both the functional responsivity of the 5-HT1B receptor, using a sumatriptan challenge paradigm, and the measured genetic variability in the locus encoding this receptor, in a study population of Alcohol Dependent men with and without Antisocial Personality Disorder. A comparison group of non-alcoholic, non-antisocial individuals, who are matched to probands on age, sex, ethnicity, and U.S. Census tract will also be studied. This latter group represents individuals who are unaffected by alcohol dependence and sociopathy, despite similar socio-environmental exposure. We believe that this approach is innovative and heuristic because it directly addresses the seential issue of the physiological ramifications of gene expression. If the serotonin 5HT1B receptor system was found to be broadly contributory to the intergenerational transmission of antisociality and substance abuse, the results would identify this system as a salient target for future genetic and psychopharmacological investigations. No less important is the possibility that psychopharmacologic agents with a high- degree of specificity for this receptor (e.g. "Triptans" such as sumatriptan) could have utility as potential therapeutics for antisocial disorders associated with substance abuse.