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

乙醇（EtOH）在环境刺激下的强化作用是滥用的主要因素 这种药物的潜力。EtOH相关的刺激在复发的动物模型中引起强烈的EtOH寻求，这些 模型被广泛用于研究乙醇渴求和复发的神经生物学基础。然而，在这方面， 来自动物模型的关于乙醇寻求中条件化因素的行为和神经生物学信息 仅限于非EtOH依赖动物或有依赖史的动物使用刺激物时的反应 在依赖诱导前适应EtOH的强化作用，而不考虑条件反射 与依赖状态下EtOH消耗量具体相关的因素。在酗酒者中， 相关性存在的历史和程度的依赖性和严重程度的饮酒冲动诱导 酒精相关的环境刺激。解释这一观察结果的一个过程是， 撤药状态下的EtOH允许了解EtOH消耗和 不良戒断症状，修改个人的强化历史，包括学习 改善/避免不利状态是EtOH强化作用的一个新的基本方面。这 该提案旨在解决这一过程对EtOH渴望和复发的影响， 主要的假设是，一个后果，撤回相关的学习（WDL）的条件效应的乙醇- 相关的环境刺激对EtOH导向行为的控制比刺激更强 条件的积极强化效果，从而发挥主导作用，在引发和维持 强迫性乙醇寻找为支持这一假设，为这一提议提供依据的初步数据 表明在戒断过程中（WDL）对EtOH可用性的刺激引起了一个显著的恢复， 方式是惩罚和努力抵抗，而乙醇寻求诱导的刺激条件乙醇 在无戒断相关学习（N-WDL）史的大鼠的非依赖状态下，则不是。的目的 拟议的项目是巩固和扩大初步调查结果，包括三个具体目标：（1）建立 环境调节对乙醇（WDL）戒断缓解的重要性 强迫性乙醇寻求，（2）确定神经元合奏介导的强迫性乙醇寻求与 WDL，并通过活性依赖性药物遗传学神经失活证实其在该行为中的作用，以及 (3)建立WDL- vs. N-中行为关键神经元集合的神经化学/表型特征， WDL动机的EtOH寻求利用RNAscope®.该项目的成功完成预计将 将WDL确定为复发脆弱性的一个主要因素，并提供必要的 为未来的研究奠定了基础，以揭示学习和神经适应性以及负责 通过与WDL相关的刺激控制EtOH寻求。

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.