The dark side of addiction: Significance of environmental conditioning to negative reinforcement by EtOH in subjects with a dependence history

乙醇(Etoh)对环境刺激的强化作用是滥用的一个主要因素 这种药物的潜力。乙醇相关刺激在复发动物模型中诱导强烈的乙醇寻求 模型被广泛用于研究酒精渴求和复发的神经生物学基础。然而， 动物模型中乙醇寻找的条件性因素的行为和神经生物学信息 仅限于乙醇非依赖动物，或在有依赖史的动物中，使用刺激 条件反射在依赖诱导前对乙醇的强化作用而不考虑条件反射 与依赖状态下的乙醇消费特别相关的因素。在酗酒者中，一个重要的积极因素 依赖的病史和程度与饮酒冲动的严重程度之间存在相关性 与酒精相关的环境刺激。解释这一观察结果的一个过程是，反复摄入 在戒断状态期间的乙醇允许学习乙醇消耗和乙醇消耗之间的负偶合 不良戒断症状，修改个人的强化历史以包括了解 改善/避免不利状态是Etoh加强行动的一个新的和基本的方面。这 该提案旨在解决这一过程对Etoh渴望和复发的影响， 主要假设是，戒断相关学习(WDL)的一个结果是乙醇的条件性效应-- 与刺激相比，相关的环境刺激对乙醇引导的行为施加了更强大的控制 仅限于积极的强化效应，从而在激发和维持方面起主导作用 强迫性的酒精追求。为了支持这一假设，为这一提议提供基础的初步数据 显示在戒断时乙醇可获得性(WDL)的条件刺激可诱导显著的恢复。 这种方式是惩罚和抗拒努力的，而刺激诱导的乙醇寻求受乙醇的制约 在无戒断相关学习(N-WDL)的大鼠的非依赖状态下，病史不是。目的 拟议的项目旨在巩固和扩大初步调查结果，涵盖三个具体目标：(1)建立 环境条件作用在乙醇戒断(WDL)启动和维持中的意义 强迫性乙醇寻求，(2)确定介导强迫性酒精寻求的神经丛与 并通过活性依赖的药物遗传神经失活来确认它们在这一行为中的作用，以及 (3)建立WDL-vs.N-的行为关键神经元集合的神经化学/表型特征。 利用RNAScope®以WDL为动机的Etoh寻人。这一项目的顺利完成预计将 将WDL确立为以前没有很好地认识到的复发易感性的主要因素，并提供必要的 为未来的研究发现学习和神经适应以及负责 与WDL相关的刺激对乙醇寻找的控制。

The conditioning of ethanol’s (EtOH) reinforcing effects with environmental stimuli is a major factor in the abuse potential of this drug. EtOH-related stimuli elicit strong EtOH seeking in animal models of relapse and these models are widely employed to study the neurobiological basis of EtOH craving and relapse. However, behavioral and neurobiological information on conditioning factors in EtOH seeking derived from animal models is limited to that from EtOH nondependent animals or, in animals with a dependence history, use of stimuli conditioned to the reinforcing effects of EtOH before dependence induction without consideration of conditioning factors related specifically to EtOH consumption in the dependent state. In alcoholics, a significant positive correlation exists between the history and degree of dependence and the severity of drinking urges induced by alcohol-related environmental stimuli. One process to explain this observation is that repeated consumption of EtOH during withdrawal states allows for learning of the negative contingency between EtOH consumption and adverse withdrawal symptoms, modifying an individual’s reinforcement history to include learning about amelioration/avoidance of adverse states as a novel and essential aspect of EtOH’s reinforcing actions. This proposal is designed to address the implications of this process with regard to EtOH craving and relapse, with the major hypothesis that a consequence of withdrawal-related learning (WDL) the conditioned effects of EtOH- associated environmental stimuli come to exert more powerful control over EtOH-directed behavior than stimuli conditioned to the positive reinforcing effects alone, and thereby play a dominant role in eliciting and maintaining compulsive EtOH seeking. In support of this hypothesis, preliminary data that provide the basis for this proposal show that stimuli conditioned to EtOH availability during withdrawal (WDL) elicit significant reinstatement in a manner that is punishment- and effort- resistant, whereas EtOH seeking induced by stimuli conditioned to EtOH in the nondependent state in rats without a withdrawal-related learning (N-WDL) history is not. The purpose of the proposed project is to solidify and extend the preliminary findings across three Specific Aims: (1) to establish the significance of environmental conditioning to withdrawal relief by EtOH (WDL) in initiating and maintaining compulsive EtOH seeking, (2) to identify neuronal ensembles mediating compulsive ethanol seeking linked to WDL and to confirm their role in this behavior via activity-dependent pharmacogenetic neural inactivation, and (3) to establish the neurochemical/phenotypic profile of behaviorally critical neuronal ensembles in WDL- vs. N- WDL-motivated EtOH seeking utilizing RNAscope®. Successful completion of this project is expected to establish WDL as a major previously not well recognized factor in relapse vulnerability and provide the necessary foundations for future studies to uncover the learning and neuroadaptive and mechanisms responsible for the control of EtOH seeking by stimuli linked to WDL.