PSYCHOSTIMULANT REGULATION OF NEURAL GENE EXPRESSION

了解可卡因产生其 影响是药物滥用研究的一个基本目标。 进展 在定义可卡因的直接生化作用时所做的， 它的行为影响，但仍有很多需要了解的 其临床相关作用的机制，特别是其 强化属性及其依赖性的产生。 显然 可卡因有非常复杂的药理作用， 需要进行大量的研究，以充分阐明其作用机制。 最近有证据表明，神经活动和精神 药物可以调节大脑中的基因表达， 这种机制可以介导神经元的长期变化， 功能 例如，可卡因给药已被证明 激活c-fos的表达，c-fos是一种细胞立即早期基因（IEG）， 老鼠的大脑 已经提出蜂窝IEG用作 转录调节因子，偶联细胞外信号的变化， 参与神经信号传导的靶基因的表达。 的 本提案的目标是描述可卡因的作用， 对IEG和编码这种IEG的候选靶基因的表达的影响 细胞特异性产物如神经递质，神经递质受体， 和神经生长因子。 IEG激活的映射将允许我们 确定可卡因的直接或间接靶细胞群 行动上 可卡因对基因表达影响的比较 相关化合物可能表明可卡因的作用机制， 与其增强性能有关。 最后，对IEG进行分析 表达与潜在靶基因的表达一起将 提供了关于核内事件级联的信息， 导致神经元功能的长期改变， 可卡因管理。 这些研究很可能是第一步， 确定可卡因诱导的神经可塑性的方面， 与行为有关，并建议对可卡因如何 在细胞和分子水平诱导基因表达的变化。

Understanding the precise mechanisms by which cocaine produces its effects is a fundamental goal of drug abuse research. Progress has been made in defining the immediate biochemical actions of cocaine as well as its behavioral effects, but much remains to be learned about the mechanisms underlying its clinically relevant actions, especially its reinforcing properties and its production of dependence. It is apparent that cocaine has a very complex pharmacology and that additional methods of study will be needed to fully delineate its mechanism of action. Recently there has been evidence that neural activity and psychotropic drugs can regulate gene expression in the brain with the implication that such mechanisms can mediate long-lasting changes in neuronal functioning. For example, cocaine administration has been shown to activate expression of c-fos, a cellular immediate early gene (IEG) in rat brain. Cellular IEG's have been proposed to function as transcriptional regulators, coupling extracellular signals to changes in expression of target genes that are involved in neural signaling. The goals of the present proposal are to characterize the effects of cocaine on expression of both IEG's and candidate target genes encoding such cell-specific products as neurotransmitters, neurotransmitter receptors, and neural growth factors. Mapping of IEG activation will allow us to define cell groups which are direct or indirect targets of cocaine action. Comparison of cocaine's effects on gene expression with other related compounds may suggest mechanisms of action for cocaine that are relevant to its reinforcing properties. Finally, analysis of IEG expression together with expression of potential target genes will provide information about the cascade of intranuclear events that could lead to long-term alterations in neuronal functioning as a result of cocaine administration. These studies are likely to be a first step in identifying aspects of cocaine-induced neural plasticity which are relevant to behavior and to suggest mechanistic studies of how cocaine induces changes in gene expression at the cellular and molecular levels.