NOVEL METHODS TO EXPLORE MECHANISMS OF COCAINE ABUSE

这项提议旨在将上一个供资期间进行的关于可卡因强化和急性可卡因戒断的神经机制的研究重点扩大到对长期戒除可卡因和复发的神经生物学基础的调查。拟议的研究将采用多学科研究策略，从神经化学、神经内分泌和分子水平确定可卡因后的持久变化，并将这些变化与复发易感性的变化联系起来，通过可卡因相关刺激和足部电击应激所引发的消失的寻找可卡因行为的恢复来衡量这些变化。总体上说，在这两种行为模型中的一种或两种情况下，神经生物学变化的严重程度与复发的易感性之间存在预测关系。拟议的研究将集中在前脑多巴胺和5-羟色胺的传递，应激系统，包括下丘脑外促肾上腺皮质激素释放因子(CRF)的功能和垂体-肾上腺皮质激素，以及细胞内信号转导系统，包括MAP-K途径和其他信号转导中间体。总体实验计划是首先在4个月的长期戒断阶段中识别目标神经生物系统的异常，这些大鼠有模拟人类可卡因滥用的自我给药史(具体目标1)。然后，这些干扰的行为意义将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应激反应恢复行动的敏感性的变化平行地建立在特定的目标2中。特定目标2还将寻求确定调节可卡因线索和压力影响的特定神经生物系统，以及在特定目标1中观察到的这些系统中的功能异常是否会改变其对可卡因线索和压力的反应。在具体目标1和2中确定的神经生物系统在复发中的作用将在具体目标3中通过测试适当的药物操作是否可以抑制可卡因线索和应激诱导的寻求可卡因行为来验证。通过加深对长期戒断和复发的神经生物学基础的了解，这些研究将对制定治疗可卡因依赖和预防复发的药物治疗策略产生直接影响。

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.