Opponent process properties of cocaine

描述（由申请人提供）：Coconut已被证明具有深刻的积极和消极的行动，密切遵守经典的“对手过程”理论的动机行为。该理论假定，双重和对立的系统协同工作，以维持情绪的稳态。事实上，在人类和动物中给予可卡因已显示出产生最初的欣快/奖励行为，随后是以快感缺乏和焦虑状态为特征的令人厌恶的“崩溃”。指导拟议研究的基本假设是，对可卡因滥用的启动、维持和恢复的基础因素的透彻理解必须包括对药物的这些双重和对立性质如何相互作用以激发寻求药物行为的理解。在这种情况下，提出了三个具体目标：具体目标1涉及旨在评估积极和消极药物线索协会的相对作用，以及药物本身的直接积极和消极作用，在恢复可卡因寻求行为在“成瘾”和“非成瘾”动物不同时期的药物戒断。具体目标2将测试的假设，积极和消极的反应可卡因和可卡因配对线索的个体差异预测动物的“风险”的药物自我管理。具体目标3描述了旨在扩展先前结果的研究，这些结果表明，“扩展杏仁核”内结构的功能性损伤可以阻止可卡因的负面/焦虑特性的表达。研究将检查NE，5-HT和CRF系统在这些结构中的作用，以确定负责可卡因的负面性质的底物，免疫细胞化学研究计划将可卡因的双重行为效应与奖励和厌恶相关的大脑区域中的神经元激活模式联系起来。这些目标中的每一个都在逻辑上建立在主要研究者实验室先前的发现之上并扩展了这些发现，并且每个目标都基于以下观点：a）可卡因寻求行为（在成瘾和非成瘾动物中）最终取决于药物固有的积极和消极特性之间的平衡，或与药物相关的刺激，B） 这种平衡决定了可卡因寻求行为的获得和复发的脆弱性，以及c）可卡因的双重作用由单独的和可识别的神经系统介导。将采用两种行为方法：可卡因自我给药的跑道模型，在同一试验的同一动物中对可卡因的混合积极和消极作用具有独特的敏感性（动物对进入与可卡因给药相关的目标框表现出接近-回避冲突）和允许分离药物的阳性和阴性性质的改良条件位置测试（动物开始喜欢与可卡因的直接效应配对的不同位置，同时避免与IV注射后15分钟存在的效应相关的位置）。当串联使用时，这两个测试提供了一个独特而强大的行为工具包，用于分离实验操作是否改变了IV可卡因的阳性和/或阴性特性。因此，拟议的研究将采用行为，药理学和免疫细胞化学方法来阐明可卡因的双重对手属性的行为和神经生物学机制，最终相互作用，以激励大鼠寻求可卡因，并在一段时间的药物戒断后恢复可卡因寻求。

DESCRIPTION (provided by applicant): Cocaine has been shown to have profound positive and negative actions that adhere closely to the classic "opponent process" theory of motivated behavior. That theory postulates that dual and opposing systems work in tandem to maintain emotional homeostasis. Indeed, cocaine administration in both humans and animals has been shown to produce an initial euphoric/rewarding action followed in time by an aversive "crash" that is characterized by states of anhedonia and anxiety. The underlying hypothesis guiding the proposed research is that a thorough understanding of the factors that underlie the initiation, maintenance and reinstatement of cocaine abuse must include an understanding of how these dual and opposing properties of the drug interact to motivate drug-seeking behavior. In this context, three specific aims are proposed: Specific Aim 1 involves studies intended to assess the relative roles of positive and negative drug-cue associations, and the drug's own direct positive and negative actions, in the reinstatement of cocaine-seeking behavior in both "addicted" and "non-addicted" animals following varying periods of drug abstinence. Specific Aim 2 will test the hypothesis that individual differences in the positive and negative responses to cocaine and cocaine-paired cues predict an animal's "risk" for drug self-administration. Specific Aim 3 describes research intended to extend previous results showing that functional lesions of structures within the "extended amygdala" can prevent the expression of cocaine's negative/anxiogenic properties. Studies will examine the roles of NE, 5-HT and CRF systems within these structures to identify the substrates responsible for cocaine's negative properties, and immunocytochemical studies are planned to link cocaine's dual behavioral effects to patterns of neuronal activation in select brain regions associated with reward and aversion. Each of these aims logically builds upon and extends previous findings from the Principal Investigator's laboratory and each is based upon the view that a) cocaine- seeking behavior (in both addicted and non-addicted animals) ultimately depends upon the balance between the inherent positive and negative properties of the drug, or stimuli associated with the drug, b) that this balance determines the vulnerability for the acquisition and relapse of cocaine-seeking behavior, and c) that the dual actions of cocaine are mediated by separate and identifiable neuronal systems. Two behavioral methods will be employed: a runway model of cocaine self-administration that is uniquely sensitive to cocaine's mixed positive and negative actions in the same animal on the same trial (animal's exhibit approach-avoidance conflict about entering a goal-box associated with cocaine administration) and a modified conditioned place test that permits for the dissociation of the positive and negative properties of the drug (animals come to prefer distinct locations paired with the immediate effects of cocaine while avoiding places associated with the effects present 15-min post IV injection). When used in tandem, these two tests provide a unique and powerful behavioral toolkit for dissociating whether an experimental manipulation alters the positive and/or the negative properties of IV cocaine. The proposed research will therefore employ behavioral, pharmacological and immunocytochemical methodologies to elucidate the behavioral and neurobiological mechanisms underlying the dual opponent properties of cocaine that ultimately interact to motivate rats to seek cocaine and to reinstate cocaine-seeking after a period of drug abstinence.