PILOT STUDY--TRANSGENIC APPROACH TO PREDILECTION OF NICOTINE ABUSE

中脑边缘多巴胺系统参与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尼古丁滥用的易感因素。这些基因包括多巴胺受体、cAMP途径的信号分子如腺苷环化酶等。许多研究人员提出的证据表明，中脑边缘多巴胺系统中cAMP途径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~y与尼古丁嗜好的确切关系仍不清楚。本研究试图通过研究转基因小鼠中由多巴胺D2受体微妙的替代突变引起的cAMP途径上调对尼古丁反应性的影响来弥合这一差距。特别是，这些研究试图创造一种表达突变D2受体的转基因小鼠，并研究突变D2受体是否会导致转基因小鼠cAMP途径上调，从而增加对尼古丁滥用的易感性。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的cAMP途径与尼古丁滥用倾向之间的因果关系。这项拟议的研究还将有助于理解多巴胺D2受体结构的细微变化是否会影响尼古丁滥用的易感性。多巴胺D2受体是中脑边缘多巴胺系统基本神经生物学功能的中介之一。

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.