Dopamine Beta-hydroxylase and Responses to Cocaine

描述（由申请人提供）：虽然可卡因滥用和成瘾是当今社会面临的严重问题，但目前还没有广泛接受的药物治疗可卡因依赖。在使用药物双硫仑的临床试验中，已观察到防止可卡因给药的显著疗效。然而，二硫仑减少可卡因使用的机制尚不清楚。根据文献以及我们实验室的初步结果，抑制多巴胺β -羟化酶（DBH）似乎是介导双硫仑临床效果的一个很好的候选靶点。DBH是在儿茶酚胺合成途径中将多巴胺转化为去甲肾上腺素的酶。抑制DBH的药物的使用，以及DBH基因基因被敲除的小鼠，将使我们能够探索这种酶在双硫仑作用中的作用。双硫仑对多种药物诱导行为的影响将被研究，包括可卡因诱导的位置偏好、厌恶、药物寻求和焦虑。了解双硫仑减少可卡因使用的作用机制将增加我们对药物成瘾的总体认识，并有助于确定未来药物开发探索的目标。

DESCRIPTION (provided by applicant): While cocaine abuse and addiction are serious problems facing our society today, there is currently no widely accepted pharmacological treatment for cocaine dependence. In clinical trials using the drug disulfiram, significant efficacy in preventing cocaine administration has been observed. However, the mechanism by which disulfiram attenuates cocaine use is unknown. Based on the literature, as well as preliminary results from our laboratory, inhibition of the enzyme Dopamine Beta-hydroxylase (DBH) appears to be a good candidate for the target which mediates disulfiram's clinical effect. DBH is the enzyme that converts dopamine to norepinephrine in the catecholamine synthetic pathway. The use of drugs that inhibit DBH, as well as mice that have genetic knockout of the Dbh gene, will enable us to explore the involvement of this enzyme in disulfiram's effects. Disulfiram's influence on multiple drug-induced behaviors will be examined including cocaine induced place preference, aversion, drug seeking, and anxiety. Understanding the mechanism of action by which disulfiram attenuates cocaine use will increase our knowledge about drug addiction in general, as well as help identify targets for future exploration in medication development.