PSYCHOSTIMULANT REGULATION OF NEURAL GENE EXPRESSION

了解可卡因产生可卡因的确切机制 影响是药物滥用研究的一个基本目标。已经取得了进展 在定义可卡因的即时生化作用以及 其行为影响，但仍有许多需要了解的 其临床相关作用的机制，特别是其 增强性质及其依赖的产生。这是显而易见的 可卡因有非常复杂的药理作用，而且其他方法 需要对其进行深入研究，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 药物可以调节大脑中的基因表达，这意味着 这种机制可以调节神经元的长期变化 功能正常。例如，可卡因的使用已被证明 激活细胞即刻早期基因c-fos的表达 老鼠的大脑。蜂窝IEG已被提出作为 转录调节因子，将细胞外信号耦合到细胞内的变化 参与神经信号传递的靶基因的表达。这个 本提案的目标是描述可卡因的影响。 编码IEG基因和候选靶基因的表达 细胞特有的产品，如神经递质，神经递质受体， 和神经生长因子。IEG激活映射将使我们能够 定义作为可卡因直接或间接目标的细胞组 行动。可卡因与其他药物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是 与其增强性能相关。最后，对IEG进行了分析 潜在目标基因的表达与表达一起将 提供有关核内事件级联的信息，这些事件可能 导致长期神经元功能改变的结果是 可卡因注射。这些研究很可能是 识别可卡因诱导的神经可塑性的哪些方面 与行为有关，并建议对可卡因如何 在细胞和分子水平上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.