Brain Mechanisms of Avoidance: Implications for Addiction

回避的大脑机制：对成瘾的影响

• 批准号: 8059730
• 负责人: JOSEPH E LEDOUX
• 金额: $ 32.51万
• 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/8059730
• 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）：尽管有大量工作，但成瘾的神经基础仍然仅部分理解。近年来，在理解药物作为积极的激励和奖励方面取得了很多进展。尽管长期以来，人们知道厌恶动机在成瘾中也起着作用，但这种角色的理解尚不清楚。与环境压力或戒断药物相关的外部刺激是负强化剂，通过加强行为，从而避免和/或避免这些刺激引起的厌恶状态，从而有助于工具药物寻求和消费反应。但是，这些大脑机制知之甚少。因此，本提案认为，对逃生/回避行为的神经基础的详细理解将提供重要的信息，从而使人们对厌恶状态在药物滥用中的作用有更深入的了解。尽管在1950年代和60年代对神经基础进行了大量研究，但这项工作不受欢迎，部分原因是结果并没有使对电路有清晰的了解。但是，在随后的几年中，详细阐明了回避第一阶段的神经基础，即帕夫洛维亚的恐惧调节。这些信息使得可以重新审视避免的神经基础。特别是，鉴于我们现在详细了解与厌恶无条件的刺激相关的中性环境刺激（US）成为一种Pavlovian条件刺激（CS），从而引起厌恶状态（恐惧，焦虑和/或压力），我们可以在这种信息上避免使用这种刺激的刺激性，尤其是在这种信息基础上，尤其是在这种信息基础上，尤其是在这种信息上，尤其是在刺激的基础上，并且是刺激性的，并且是刺激性的，并且是刺激性的，尤其是刺激性的情况。避免条件也使用了帕夫洛维亚调节的神经基础。研究将研究杏仁核（杏仁核）的贡献，杏仁核是恐惧条件的关键结构，对避免。重点将放在与恐惧条件相关的特定核的可能作用上接管（尤其是背侧纹状体），最后，恐惧和回避中个体差异的作用及其在预测成瘾和复发易感性方面的价值。 公共卫生相关性：滥用药物是现代社会的重大问题。更好地了解成瘾和复发的大脑机制应提供新的见解，从而导致更好的预防和治疗手段。受到较少关注的一个领域是负面强化和避免在成瘾和复发中的作用，这是该提案的主要重点。