PILOT STUDY--TRANSGENIC APPROACH TO PREDILECTION OF NICOTINE ABUSE

试点研究——通过转基因方法降低尼古丁滥用倾向

• 批准号: 6349046
• 负责人: QUN-YONG ZHOU
• 金额: $ 17.27万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349046
• 关键词: cyclic AMP; dopamine receptor; drug addiction; embryonic stem cell; gene expression; gene mutation; gene targeting; genetic susceptibility; genetically modified animals; genotype; laboratory mouse; limbic system; microinjections; nicotine; receptor expression; tissue /cell culture; tobacco abuse

The mesolimbic dopamine system mediates the reinforcing effects of nicotine and other drugs of abuse. Thus the genes affecting the functionality of the mesolimbic dopamine system can be contributing factors to predisposition to nicotine abuse. These genes include dopamine receptors, signaling molecules of cAMP pathway such as adenylate cyclase, and others. Evidence put forth by a number of investigators suggests that the difference in the different biochemical profile of cAMP pathway in the mesolimbic dopamine system may result in differential predilection to abused drugs. The precise relation of up-regulated cAMP signaling pathway~y and nicotine predilection, however, remains vague. The present study seeks to bridge this gap by investigating the consequence of up-regulated cAMP pathway in transgenic mice, caused by a subtle substitution mutation in the dopamine D2 receptor, on nicotine responsiveness. Particularly, these studies seek to produce a strain of transgenic mice that express the mutant D2 receptor and to investigate whether the mutant D2 receptor will result in up-regulation of cAMP pathway in transgenic mice and therefore increased vulnerability to nicotine abusing. The availability of transgenic mice expressing the mutant D2 receptor will help establish the causal effect relationship of an up- regulated cAMP pathway and predilection to nicotine abuse. The proposed studies will also lead to an understanding of whether a subtle change in structure of dopamine D2 receptor, one of mediators for the basic neurobiological function of mesolimbic dopamine system, may affect predisposition to nicotine abuse.

中脑边缘多巴胺系统介导尼古丁和其他滥用药物的强化作用。 因此，影响中脑边缘多巴胺系统功能的基因可能是导致尼古丁滥用倾向的因素。 这些基因包括多巴胺受体、cAMP途径的信号分子如腺苷酸环化酶等。 许多研究者提出的证据表明，中脑边缘多巴胺系统中cAMP途径的不同生化特征的差异可能导致对滥用药物的差异偏好。然而，上调的cAMP信号通路与尼古丁偏好的确切关系仍不清楚。本研究旨在通过研究转基因小鼠中由多巴胺D2受体的微妙取代突变引起的上调cAMP途径对尼古丁反应性的影响来弥合这一差距。特别地，这些研究试图产生表达突变D2受体的转基因小鼠品系，并研究突变D2受体是否会导致转基因小鼠中cAMP途径的上调，从而增加对尼古丁滥用的脆弱性。表达突变D2受体的转基因小鼠的可用性将有助于建立上调cAMP途径与尼古丁滥用偏好之间的因果关系。拟议的研究还将导致对多巴胺D2受体结构的微妙变化的理解，多巴胺D2受体是中脑边缘多巴胺系统的基本神经生物学功能的介质之一，是否可能影响尼古丁滥用的易感性。