Neural Mechanism by which Punishment Modulates Drug-Seeking

惩罚调节药物寻求的神经机制

• 批准号: 8386233
• 负责人: THOMAS C JHOU
• 金额: $ 22.13万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386233
• 关键词: Ablation; Addictive Behavior; Affective; Animals; Anxiety; Area; Automobile Driving; Aversive Stimulus; Behavior; Behavior Disorders; Brain; Brain region; Cell Nucleus; Characteristics; Cocaine; Cocaine Dependence; Cognitive; Data; Educational process of instructing; Elements; Employee Strikes; Fiber; Food; Fright; Future; Human; Impairment; Individual; Individual Differences; Learning; Lesion; Midbrain structure; Modeling; Neurons; Outcome; Pathology; Pattern; Pharmaceutical Preparations; Phenotype; Primates; Punishment; Rattus; Reporting; Resistance; Rewards; Role; Shock; Signal Transduction; Stimulus; Structure; Testing; Time; Toxic effect; Variant; Withdrawal; abstracting; addiction; adverse outcome; awake; clinically relevant; cost; design; dopaminergic neuron; drug addict; drug reward; endophenotype; neuromechanism; optogenetics; social

DESCRIPTION (provided by applicant): One of the defining features of addictive behavior is its persistence despite potentially severe adverse outcomes. To further understand why addicts fail to learn from negative outcomes, we propose to explore the role of a newly identified brain region, the rostromedial tegmental nucleus (RMTg), which we and others have recently shown to encode negative reward prediction errors, and to be critically involved in a variety of aversive behaviors. We hypothesize that impairment of this structure leads to an addiction phenotype in which animals persistently seek outcomes despite aversive outcomes. We propose two aims, the first of which is designed to better understand the basic mechanisms by which the RMTg contributes to learning about negative outcomes. Our second aim is more translational, exploring the role of the RMTg in cocaine-seeking under punishment, as well as its contribution to individual variation in propensity to develop addictive behaviors. PUBLIC HEALTH RELEVANCE: One hallmark of an addictive behavior is its persistence despite large negative outcomes, which can take a variety of forms, include physically aversive outcomes (withdrawal, toxicity) or social, cognitive, and financial losses. To better understand the pathology underlying these behaviors, we will explore the mechanisms underlying our recent findings that lesions of the rostromedial tegmental nucleus (RMTg) render animals strikingly deficient in learning from aversive outcomes. This will facilitate better treatments for behavioral disorders in which individuals seek drug rewards despite the large costs they incur.

描述（由申请人提供）：成瘾行为的定义特征之一是尽管可能产生严重的不良后果，但其持续存在。为了进一步理解为什么成瘾者无法从负面结果中学习，我们建议探索新发现的大脑区域，即嘴内侧被盖核（RMTg）的作用，我们和其他人最近证明该区域编码负面奖励预测错误，并且将其严重参与各种令人厌恶的事情 行为。我们假设这种结构的损伤会导致成瘾表型，其中动物尽管厌恶结果却坚持不懈地寻求结果。我们提出了两个目标，第一个目标是为了更好地理解 RMTg 有助于了解负面结果的基本机制。我们的第二个目标更具转化性，探索 RMTg 在惩罚下寻求可卡因中的作用，以及它对发展成瘾行为倾向的个体差异的贡献。 公共健康相关性：成瘾行为的一个标志是，尽管会带来很大的负面后果，但它仍会持续存在，负面后果可能有多种形式，包括身体厌恶的结果（戒断、毒性）或社交、认知和经济损失。为了更好地理解这些行为背后的病理学，我们将探讨我们最近发现的机制，即头内侧被盖核（RMTg）的损伤使动物在从厌恶结果中学习方面显着缺乏。这将有助于更好地治疗行为 在这种疾病中，尽管付出了巨大的代价，人们仍然寻求药物奖励。