PILOT STUDY--TRANSGENIC APPROACH TO PREDILECTION OF NICOTINE ABUSE

中脑边缘多巴胺系统介导尼古丁和其他滥用药物的增强作用。 因此，影响中脑边缘多巴胺系统功能的基因可能是尼古丁滥用倾向的促成因素。 这些基因包括多巴胺受体、cAMP途径的信号分子（例如腺苷酸环化酶）等。 许多研究人员提出的证据表明，中脑边缘多巴胺系统中 cAMP 通路的不同生化特征的差异可能导致对滥用药物的不同偏好。然而，上调的 cAMP 信号通路与尼古丁偏好之间的确切关系仍然模糊。本研究旨在通过调查转基因小鼠中由多巴胺 D2 受体的微妙取代突变引起的 cAMP 通路上调对尼古丁反应的影响来弥补这一差距。特别是，这些研究试图产生表达突变型 D2 受体的转基因小鼠品系，并研究突变型 D2 受体是否会导致转基因小鼠中 cAMP 通路上调，从而增加尼古丁滥用的脆弱性。表达突变型 D2 受体的转基因小鼠的出现将有助于建立上调的 cAMP 通路与尼古丁滥用倾向之间的因果关系。拟议的研究还将有助于了解多巴胺 D2 受体（中脑边缘多巴胺系统基本神经生物学功能的介质之一）结构的微妙变化是否可能影响尼古丁滥用的倾向。

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.