NOVEL METHODS TO EXPLORE MECHANISMS OF COCAINE ABUSE

探索可卡因滥用机制的新方法

• 批准号: 6515507
• 负责人: Friedbert Weiss
• 金额: $ 41.67万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515507
• 关键词: behavior test; behavioral /social science research tag; behavioral extinction; cocaine; corticotropin releasing factor; cues; disease /disorder model; dopamine; drug addiction; drug withdrawal; laboratory rat; mitogen activated protein kinase; neurophysiology; neurotransmitter transport; prosencephalon; psychopharmacology; reinforcer; relapse /recurrence; self medication; serotonin; synapses

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.

这项建议旨在将上一个供资期间进行的研究重点扩大到调查可卡因长期戒断和复吸的神经生物学基础，这些研究涉及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的研究策略，以确定持久的可卡因后的变化在神经化学，神经内分泌和分子水平，并将这些扰动的变化，复发的脆弱性，通过恢复可卡因相关的刺激引起的寻求可卡因的行为，和footshock应力测量。 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。 拟议的研究将集中在前脑多巴胺和5-羟色胺传输，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-激酶途径和其他信号转导中间体。 总体实验计划是首先在具有可卡因自我给药史的大鼠（模拟人类可卡因狂欢滥用）中，在4个月的长期戒断期内鉴定靶向神经生物学系统的异常（具体目标1）。 这些障碍的行为意义将在具体目标2中通过检查这些变化或其在长期戒断过程中的缓解是否被可卡因线索和压力的反应恢复作用的易感性变化所掩盖来确定。 具体目标2还将寻求确定特定的神经生物学系统，介导可卡因线索和压力的影响，以及在具体目标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。 具体目标1和2中确定的神经生物学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理学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吸的神经生物学基础的理解，这些研究将对制定治疗可卡因依赖和预防复吸的药物治疗策略产生直接影响。