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 前脑末端区域的神经传递。 实验室研究 分子和细胞神经科学的研究强调了 多巴胺作用的分子机制，并确定了一种蛋白质 激酶/蛋白磷酸酶级联反应是细胞内 多巴胺神经传递的途径。 该项目旨在分析 这种级联在可卡因的急性和慢性作用中的作用， 安非他明 所提出的实验利用缺乏 突触后多巴胺信号通路的特定成分; 编码磷酸酶抑制剂DARPP-32和抑制剂-1的基因。 这些小鼠代表了唯一缺乏已知细胞内 并提供独特资源， 研究多巴胺能信号改变在急性和慢性 滥用药物的影响。 拟议的研究将审查以下方面的作用： DARPP-32和抑制剂-1介导或调节（a） 可卡因和安非他明对已知多巴胺调节的 细胞内靶点。 (b)精神刺激和奖励特性 可卡因和安非他明的神经毒性作用和（c）取代的 安非他明 本项目的总体目标是获得进一步的洞察力 神经化学机制，在人类 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.