Opponent process properties of cocaine

描述(申请人提供)：可卡因已被证明具有深刻的积极和消极行为，密切遵守经典的“对手过程”理论的动机行为。这一理论假设，二元系统和对立系统协同工作，以维持情绪的动态平衡。事实上，人类和动物服用可卡因都被证明会产生一种最初的愉悦/有益的行为，随后是一种以快感缺失和焦虑为特征的令人厌恶的“崩溃”。指导这项拟议研究的基本假设是，彻底了解引发、维持和恢复可卡因滥用的因素必须包括了解药物的这些双重和对立的属性如何相互作用，以激励寻求毒品的行为。在这方面，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联系以及药物本身的直接积极和消极作用在戒毒不同时期后恢复“上瘾”和“非上瘾”动物寻找可卡因行为方面的相对作用的研究。《特定目标2》将检验这样一种假设，即对可卡因和可卡因配对线索的积极和消极反应的个体差异预测了动物自我给药的风险。具体目标3描述了旨在扩展先前结果的研究，该结果表明，“扩大的杏仁核”内结构的功能性损害可以防止可卡因的负面/焦虑特性的表达。研究将研究NE、5-HT和CRF系统在这些结构中的作用，以确定导致可卡因负面特性的底物，并计划进行免疫细胞化学研究，将可卡因的双重行为效应与与奖赏和厌恶相关的特定大脑区域的神经元激活模式联系起来。这些目标中的每一个都合乎逻辑地建立和扩展了首席调查员实验室以前的发现，并且每个目标都基于这样的观点：a)寻求可卡因的行为(在上瘾和非上瘾的动物中)最终取决于药物固有的积极和消极属性之间的平衡，或与药物相关的刺激，b) 这种平衡决定了可卡因寻找行为的易得性和复发性，以及c)可卡因的双重作用是由独立的和可识别的神经系统介导的。将采用两种行为方法：跑道上的可卡因自我给药模型，它对同一动物在同一试验中可卡因的积极和消极混合作用特别敏感(动物的展示方法-进入与可卡因给药相关的目标盒的回避冲突)，以及修改的条件位置测试，允许分离药物的积极和消极属性(动物开始更喜欢与可卡因的直接影响配对的不同位置，而避免与静脉注射后15分钟的效果相关的地方)。当同时使用这两个测试时，这两个测试提供了一个独特而强大的行为工具包，用于分离实验性操作是否改变了静脉注射可卡因的积极和/或消极属性。因此，这项拟议的研究将使用行为、药理学和免疫细胞化学方法来阐明可卡因的双重对抗特性背后的行为和神经生物学机制，这些特性最终相互作用，促使大鼠寻找可卡因，并在一段时间戒毒后恢复寻找可卡因。

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.