DARPP/32 AND INHIBITOR-1 KNOCKOUT MICE

可卡因和安非他明的急性和慢性作用被认为是 在很大程度上，是通过增加多巴胺来实现的 前脑终末区的神经传递。实验室中的研究 分子和细胞神经科学的研究重点是 多巴胺作用的分子机制，并确定了一种蛋白质 激酶/蛋白磷酸酶级联作为细胞内的主要途径之一 多巴胺神经传递的途径。该项目建议分析 这种级联反应在可卡因和可卡因的急性和慢性作用中的作用 安非他命。建议的实验利用缺乏的小鼠品系。 突触后多巴胺信号通路的特殊成分； 编码磷酸酶抑制物DARPP-32和抑制物-1的基因。 这些小鼠代表了唯一一种缺乏已知的细胞内 多巴胺作用的目标，并提供独特的资源，用于 多巴胺能信号改变在急慢性脑损伤中的作用研究 滥用药物的影响。拟议的研究将审查 DARPP-32和抑制物-1在介导或调制(A) 可卡因和苯丙胺对已知多巴胺调节的磷酸化的影响 细胞内目标。(B)精神运动兴奋剂和奖励性质 可卡因和安非他明的毒性以及(C)取代的神经毒性作用 安非他明。这个项目的总体目标是获得进一步的洞察力 在人体内起关键作用的神经化学机制 滥用药物。

The acute and chronic actions of cocaine and amphetamine are thought to be mediated, in large measure, through augmentation of dopamine neurotransmission in forebrain terminal fields. Research in The laboratory of Molecular and Cellular Neuroscience has emphasized athe study of the molecular mechanisms of dopamine action and has identified a protein kinase/protein phosphatase cascade as one of the major intracellular pathways for dopamine neurotransmission. This project proposes to analyze the role of this cascade in the acute and chronic actions of cocaine and amphetamine. The proposed experiments utilize mouse strains lacking particular components of the postsynaptic dopamine signaling pathway; the genes coding for the phosphatase inhibitors, DARPP-32 and inhibitor-1. These mice represent the only animal models lacking a known intracellular target for dopamine action and provide a unique resource with which to study the role of altered dopaminergic signaling in the a c ute and chronic effects of drugs of abuse. The proposed studies will examine the role of DARPP-32 and inhibitor-1 in mediating or modulating (a) the effects of cocaine and amphetamine on the phosphorylation of known dopamine-regulated intracellular targets. (b) the psychomotor stimulant and reward properties of cocaine and amphetamine and (c) the neurotoxic actions of substituted amphetamines. The overall goal of this project is to gain further insight into the neurochemical mechanisms that play critical roles in human substance abuse.