Brain Mechanisms of Avoidance: Implications for Addiction

回避的大脑机制：对成瘾的影响

• 批准号: 8261936
• 负责人: JOSEPH E LEDOUX
• 金额: $ 32.3万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261936
• 关键词: Amygdaloid structure; Animals; Anxiety; Area; Attention; Auditory; Avoidance Learning; Basal Ganglia; Behavior; Behavioral inhibition; Brain; Breeding; Cell Nucleus; Conditioned Stimulus; Consumption; Corpus striatum structure; Cues; Data; Dorsal; Drug Sensitization; Freezing; Fright; Goals; Habits; Hippocampus (Brain); Human; Incentives; Individual Differences; Lateral; Lead; Learning; Left; Lesion; Light; Literature; Mediating; Motivation; National Institute of Drug Abuse; Negative Reinforcements; Negative Reinforcer; Nucleus Accumbens; Operant Conditioning; Outcome; Output; Pathway interactions; Performance; Pharmaceutical Preparations; Phase; Play; Predisposition; Prevention; Process; Psychological reinforcement; Rat Strains; Relapse; Request for Applications; Research; Rewards; Role; Shock; Signal Transduction; Societies; Staging; Stimulus; Stress; Structure; Substance abuse problem; Testing; Training; Work; addiction; avoidance behavior; base; classical conditioning; conditioned fear; conditioning; drug withdrawal; insight; neural circuit; neuromechanism; public health relevance; relating to nervous system; response

DESCRIPTION (provided by applicant): In spite of massive amounts of work, the neural basis of addiction remains only partly understood. Much progress has been made in recent years in understanding the motivational role of drugs as positive incentives and rewards. Although it has long known that aversive motivation also plays a role in addiction, this role has been less clearly understood. External stimuli associated with environmental stress or drug withdrawal are negative reinforcers that contribute to instrumental drug seeking and consumption responses by strengthening behaviors that allow escape from and/or avoidance of the aversive states elicited by these stimuli. However, little is known about these brain mechanisms; for this reason, the present proposal argues that a detailed understanding of the neural basis of escape/avoidance behavior will provide important information that will allow a deeper understanding of the role of aversive states in substance abuse. While much research was conducted on the neural basis avoidance in the 1950s and 60s, this work fell out of favor, in part because the results did not lead to a clear understanding of the circuitry. However, in the intervening years, the neural basis of the first phase of avoidance, Pavlovian fear conditioning, has been elucidated in detail. This information makes it possible to revisit the neural basis of avoidance in a new light. In particular, given that we now understand in detail the neural mechanisms through which a neutral environmental stimulus associated with an aversive unconditioned stimulus (US) becomes a Pavlovian conditioned stimulus (CS) that elicits aversive states (fear, anxiety and/or stress), we can now build on this information to understand the neural basis of avoidance conditioning, especially if the same stimuli used as CSs and USs (tone an shock) in studies of the neural basis of Pavlovian conditioning are also used in avoidance conditioning. The studies will examine the contribution of the amygdala, a key structure for fear conditioning, to avoidance. The focus will be on the possible role of specific nuclei implicated in fear conditioning in the acquisition and performance of avoidance (especially the lateral, basal and central nuclei), the contribution of anatomical outputs of key amygdala nuclei (especially the projection from the basal amygdala to the nucleus accumbens), whether avoidance becomes an amygdala-independent habit following over-training, and if so whether other areas take over (especially the dorsal striatum), and finally the role of individual differences in fear and avoidance and their value in predicting susceptibility to addiction and relapse. PUBLIC HEALTH RELEVANCE: Substance abuse is a significant problem in modern society. Better understanding of the brain mechanisms underlying addiction and relapse should provide new insights that could lead to better means of prevention and treatment. One area that has received less attention is the role of negative reinforcement and avoidance in addiction and relapse, the main focus of this proposal.

描述（由申请人提供）：尽管做了大量的工作，但成瘾的神经基础只被部分理解。近年来，在理解药物作为积极激励和奖励的激励作用方面取得了很大进展。尽管人们早就知道厌恶动机在成瘾中也起作用，但人们对这一作用的理解却不太清楚。与环境压力或药物戒断相关的外部刺激是负强化因素，通过强化允许逃避和/或避免这些刺激引起的厌恶状态的行为，有助于工具性药物寻求和消费反应。然而，人们对这些大脑机制知之甚少；因此，本研究认为，对逃避/回避行为的神经基础的详细了解将提供重要的信息，使我们能够更深入地了解厌恶状态在药物滥用中的作用。虽然在20世纪50年代和60年代进行了大量关于神经基础回避的研究，但这项工作不受欢迎，部分原因是研究结果没有导致对电路的清晰理解。然而，在这中间的几年里，回避的第一阶段的神经基础，巴甫洛夫恐惧条件反射，已经被详细阐明。这一信息使我们有可能重新审视回避的神经基础。特别是，鉴于我们现在详细了解了中性环境刺激与厌恶的非条件刺激（US）相关联成为引发厌恶状态（恐惧、焦虑和/或压力）的巴甫洛夫条件刺激（CS）的神经机制，我们现在可以基于这些信息来理解回避条件反射的神经基础。尤其是在巴甫洛夫条件反射的神经基础研究中用作CSs和USs（音调和电击）的刺激也用于回避条件反射。这些研究将检验杏仁核在逃避行为中的作用，杏仁核是控制恐惧的关键结构。重点将放在与恐惧条件反射有关的特定核在回避的获得和表现中的可能作用（特别是外侧核，基底核和中央核），关键杏仁核的解剖输出的贡献（特别是从基底杏仁核到伏隔核的投影），回避是否在过度训练后成为一种独立于杏仁核的习惯，如果是这样，是否其他区域接管（特别是背纹状体），最后是个体差异在恐惧和回避中的作用以及它们在预测成瘾易感性和复吸方面的价值。