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: 10321914
• 负责人: Friedbert Weiss
• 金额: $ 39.7万
• 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/10321914
• 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; abuse liability; 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.

环境刺激对乙醇 (EtOH) 增强作用的调节是滥用的一个主要因素 这种药物的潜力在复发的动物模型中引起强烈的乙醇相关刺激。 模型被广泛用于研究乙醇渴望和复发的神经生物学基础。 来自动物模型的乙醇寻求调节因素的行为和神经生物学信息 仅限于来自 EtOH 非依赖性动物，或者在有依赖性历史的动物中，使用刺激 在依赖性诱导之前调节乙醇的增强作用，而不考虑调节 与酒精依赖状态下的乙醇消耗相关的因素，对酗酒者来说是一个显着的积极影响。 依赖史和依赖程度与饮酒冲动的严重程度之间存在相关性 解释这一观察结果的一个过程是重复饮酒。 戒断状态期间的 EtOH 允许了解 EtOH 消耗和 不良戒断症状，​​修改个人的强化历史，包括了解 改善/避免不良状态是 EtOH 强化行动的一个新颖且重要的方面。 该提案旨在解决这一过程对乙醇渴望和复发的影响， 主要假设是戒断相关学习（WDL）的结果是乙醇的条件效应 与环境刺激相比，相关的环境刺激对乙醇导向的行为具有更强大的控制作用 只适应于积极的强化效应，从而在引发和维持 为了支持这一假设，初步数据为本提案提供了基础。 表明，在戒断期间（WDL）以乙醇可用性为条件的刺激会引起显着的恢复 的方式是抵抗惩罚和努力的，而乙醇寻求是由以乙醇为条件的刺激引起的 在没有戒断相关学习（N-WDL）史的大鼠中，处于非依赖性状态不是目的。 拟议项目旨在巩固和扩展三个具体目标的初步调查结果：(1) 建立 环境调节对 EtOH (WDL) 戒断缓解在启动和维持中的重要性 强迫性乙醇搜寻，(2) 识别介导强迫性乙醇搜寻的神经元群 WDL 并通过活性依赖性药物遗传学神经失活来确认其在这种行为中的作用，以及 (3) 建立 WDL- 与 N- 中行为关键神经元的神经化学/表型概况 WDL 驱动的 EtOH 利用 RNAscope® 预计将成功完成。 将 WDL 确定为先前未得到充分认识的复发脆弱性的主要因素，并提供必要的 为未来的研究奠定基础，以揭示学习和神经适应性以及负责的机制 通过与 WDL 相关的刺激来控制 EtOH 寻找。