NOVEL METHODS TO EXPLORE MECHANISMS OF COCAINE ABUSE

这项建议试图将上一供资期间所进行的研究的重点扩大到对长期可卡因戒断和复发的神经生物学基础的调查，这些研究是关于可卡因强化和可卡因急性戒断的神经机制。拟议的研究将采用多学科研究策略，以确定在神经化学、神经内分泌和分子水平上持续的可卡因后变化，并将这些扰动与易感性的变化联系起来，这些易感性的变化是由可卡因相关刺激和足部冲击应激引起的已消失的可卡因寻求行为的恢复所测量的。总的假设是，在这些行为模型中的一个或两个中，神经生物学变化的严重程度和复发的易感性之间存在预测关系。建议的研究将集中在前脑多巴胺和血清素的传递，应激系统包括下丘脑外促肾上腺皮质激素释放因子（CRF）功能和垂体-肾上腺皮质激素，以及细胞内信号转导系统包括MAP-激酶途径和其他信号转导中间体。总体实验计划是首先在有可卡因自我给药史的大鼠中，通过4个月的长期戒断期，确定目标神经生物学系统的异常，这些大鼠模仿人类可卡因暴滥用（Specific Aim 1）。这些干扰的行为意义将在具体目标2中建立，通过检查这些变化，或它们在长期戒断过程中的缓解，是否与对可卡因线索和压力的反应恢复行为的易感性变化相平行。Specific Aim 2还将寻求确定介导可卡因线索和压力效应的特定神经生物学系统，以及在Specific Aim 1中观察到的这些系统的功能异常是否会改变它们对可卡因线索和压力的反应。在特异性目标1和2中确定的神经生物学系统复发中的作用将在特异性目标3中通过测试适当的药理操作是否可以抑制可卡因线索和压力诱导的可卡因寻求行为来验证。通过增加对长期戒断和复发的神经生物学基础的理解，这些研究将对治疗可卡因依赖和预防复发的药物治疗策略的发展具有直接意义。

This proposal seeks to extend the focus of studies conducted during the previous funding period which were concerned with neural mechanisms of cocaine reinforcement and acute cocaine withdrawal, to an investigation of the neurobiological basis of protracted cocaine withdrawal and relapse. The proposed studies will employ a multidisciplinary research strategy to identify enduring post-cocaine changes at the neurochemical, neuroendocrine, and molecular level and to relate these perturbations to changes in the vulnerability to relapse as measured by the reinstatement of extinguished cocaine-seeking behavior elicited by cocaine-associated stimuli, and footshock stress. The overall hyposthesis is that a predictive relationship exists between the severity of neurobiologic changes and the susceptibility to relapse in one or both of these behavioral models. The proposed studies will focus on forebrain dopamine and serotonin transmission, stress systems including extrahypothalamic corticotropin-releasing factor (CRF) function and pituitary-adrenocortical hormones, as well as on intracellular signal transduction systems including the MAP- kinase pathway and other signal transduction intermediates. The overall experimental plan is to first identify abnormalities in the targeted neurobiological systems throughout a 4 month protracted withdrawal phase in rats with a history of cocaine self-administration that mimics human cocaine binge abuse (Specific Aim 1). The behavioral significance of these disturbances will then be established in Specific Aim 2 by examining whether these changes, or their remission over the course of protracted abstinence, are paralleled by changes in susceptibility to the response-reinstating actions of cocaine cues and stess. Specific Aim 2 will also seek to identify specific neurobiological systems that mediate the effects of cocaine cues and stress, and whether functional abnormalities in these systems observed in Specific Aim 1 alter their response cocaine cues and stress. The role in relapse of neurobiological systems identified in Specific Aims 1 and 2 will then be verified in Specific Aim 3 by testing whether appropriate pharmacological manipulations can inhibit cocaine-seeking behavior induced by cocaine cues and stress. By increasing understanding of the neurobiological basis of protracted abstinence and relapse, these studies will have direct implications for the development of pharmacotherapeutic strategies for treatment of cocaine dependence and prevention of relapse.