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

成瘾的阴暗面：环境调节对有成瘾史的受试者中乙醇负强化的意义

• 批准号: 10077806
• 负责人: Friedbert Weiss
• 金额: $ 39.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077806
• 关键词: Addictive Behavior; Address; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Animal Model; Animals; Behavior; Behavioral; Brain region; Chronic; Complement; Cues; Data; Dependence; Development; Dimensions; Distress; Ethanol; Ethanol dependence; Foundations; Future; Individual; Lead; Learning; Link; Location; Measures; Mediating; Modeling; Motivation; Nature; Negative Reinforcements; Neurobiology; Neurons; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Play; Process; Psychological reinforcement; Punishment; Rattus; Recording of previous events; Relapse; Resistance; Role; Severities; Side; Stimulus; Withdrawal; Withdrawal Symptom; Work; addiction; alcohol availability; alcohol craving; alcohol effect; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; classical conditioning; conditioning; craving; design; drinking; experience; improved; insight; neurobehavioral; neurochemistry; novel; problem drinker; recruit; relating to nervous system; research and development; treatment strategy

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.

乙醇（ETOH）对环境刺激的增强作用是滥用的主要因素 这种药物的潜力。 EtOH相关的刺激引起了强烈的ETOH寻求浮雕模型，这些刺激在 模型被广泛用于研究ETOH渴望和救济的神经生物学基础。然而， 有关ETOH寻求从动物模型衍生的条件因素的行为和神经生物学信息 仅限于eTOH非依赖性动物或具有依赖史的动物的使用限制 在依赖诱导之前不考虑条件之前，以ETOH的增强作用为条件 与依赖状态的ETOH消耗特别相关的因素。在酗酒者中，很大的积极 历史与依赖程度与饮酒的严重程度之间存在相关性 酒精相关的环境刺激。解释这一观察的一个过程是重复消费 撤回状态期间的eTOH允许学习ETOH消耗和 不良戒断症状，​​修改个人的增强历史以包括学习 改善/避免广告状态是Etoh加强行动的新颖和基本方面。这 建议旨在解决此过程在Etoh渴望和继电器方面的含义， 主要假设是撤回相关学习的结果（WDL）eTOH-的条件作用 相关的环境刺激比刺激更强大地控制ETOH指导行为 仅凭积极的增强效应，从而在引发和维护中起主要作用 强迫性ETOH寻求。为了支持这一假设，为该提案提供了基础的初步数据 证明戒断过程中以etoH的可用性为条件的刺激（WDL）在A 惩罚和努力的方式，而ETOH寻求由ETOH的刺激引起的 在没有戒断相关学习（N-WDL）历史的大鼠中的非依赖性状态下。目的 拟议的项目是巩固和扩展三个特定目标的初步发现：（1）建立 环境条件对通过ETOH（WDL）启动和维护提取撤回的意义 强迫性ETOH寻求，（2）确定介导强迫性乙醇寻求与之相关的神经元合奏 WDL并通过依赖活性的药物遗传神经元失活而确认其在这种行为中的作用，并且 （3）在WDL-vs.N-中建立行为关键神经元集合的神经化学/表型谱 WDL动机的ETOH寻求利用RNASCOPE®。该项目的成功完成将有望 建立WDL作为以前没有公认的救济脆弱性因素，并提供必要的因素 未来研究的基础，以揭示负责的学习和神经适应性和机制 通过与WDL相关的刺激来控制ETOH寻求。