Opponent process properties of cocaine

可卡因的对手加工特性

• 批准号: 8788825
• 负责人: AARON ETTENBERG
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788825
• 关键词: Amygdaloid structure; Anhedonia; Animals; Anxiety; Behavior; Behavioral; Behavioral Mechanisms; Biological Assay; Boxing; Brain; Brain region; Cocaine; Cocaine Abuse; Corticotropin-Releasing Hormone; Cues; Data; Dissociation; Drug effect disorder; Emotional; Environment; Equilibrium; Exhibits; Goals; Habenula; Health; Homeostasis; Human; Individual Differences; Injection of therapeutic agent; Laboratories; Lateral; Lesion; Link; Location; Maintenance; Mediating; Methodology; Methods; Modeling; Nature; Negative Reinforcements; Neurobiology; Neurons; Organism; Pharmaceutical Preparations; Principal Investigator; Procedures; Process; Property; Rattus; Reaction; Relapse; Relative (related person); Research; Research Personnel; Rewards; Risk; Role; Self Administration; Self-Administered; Serotonin; Speed; Stimulus; Structure; System; Testing; Time; Work; approach avoidance behavior; base; conditioning; drug abstinence; drug seeking behavior; motivated behavior; neurobiological mechanism; neurochemistry; neuronal patterning; noradrenergic; preference; prevent; relating to nervous system; response; stem; theories; willingness

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.

描述（由申请人提供）：可卡因已被证明具有深刻的积极和消极作用，这与经典的“对手过程”动机行为理论密切相关。该理论假定双重和对立的系统协同工作以维持情绪的内稳态。事实上，人类和动物服用可卡因都会产生一种最初的愉悦/奖励行为，随后是一种以快感缺乏和焦虑状态为特征的厌恶“崩溃”。指导拟议研究的基本假设是，对可卡因滥用开始、维持和恢复的潜在因素的透彻理解必须包括对药物的这些双重和对立特性如何相互作用以激发寻求药物行为的理解。在此背景下，提出了三个具体目标：具体目标1涉及旨在评估“成瘾”和“非成瘾”动物在不同时期戒断毒品后恢复可卡因寻求行为的积极和消极药物线索关联以及药物本身的直接积极和消极作用的相对作用。具体目标2将测试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动物自我给药的“风险”的假设。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”内结构的功能性病变可以阻止可卡因的阴性/焦虑特性的表达。研究将检查NE、5-羟色胺和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，免疫细胞化学研究计划将可卡因的双重行为效应与大脑中与奖励和厌恶相关的特定区域的神经元激活模式联系起来。这些目标在逻辑上都建立在并扩展了首席研究员实验室之前的发现，并且每个目标都基于这样的观点：a)可卡因寻求行为（在成瘾和非成瘾的动物中）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