PILOT STUDY--TRANSGENIC APPROACH TO PREDILECTION OF NICOTINE ABUSE

中脑边缘多巴胺系统调节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通路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，cAMP信号通路~y上调与尼古丁偏好的确切关系尚不清楚。本研究试图通过研究转基因小鼠中cAMP通路上调的后果来弥合这一差距，cAMP通路上调是由多巴胺D2受体的微妙替代突变引起的，对尼古丁的反应性。特别是，这些研究试图产生一种表达D2受体突变的转基因小鼠品系，并研究D2受体突变是否会导致转基因小鼠cAMP通路上调，从而增加尼古丁滥用的易感性。表达D2受体突变体的转基因小鼠的可用性将有助于建立cAMP通路上调与尼古丁滥用倾向之间的因果关系。这些研究也将有助于了解多巴胺D2受体结构的细微变化是否会影响尼古丁滥用的倾向，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介质之一。

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.