Brain Mechanisms of Avoidance: Implications for Addiction

描述(由申请者提供)：尽管有大量的工作，但成瘾的神经基础仍然只有部分了解。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。尽管很早就知道厌恶动机在上瘾中也起到了作用，但人们对这种作用的认识还不是很清楚。与环境应激或戒毒相关的外部刺激是负性强化因素，通过加强行为以逃避和/或避免由这些刺激引起的厌恶状态，从而促进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，本提案认为，详细了解逃避/回避行为的神经基础将提供重要信息，使我们能够更深入地了解厌恶状态在物质滥用中的作用。虽然在20世纪50年代和60年代进行了许多关于神经基础回避的研究，但这项工作没有得到人们的青睐，部分原因是结果没有导致对电路的清楚理解。然而，在其间的几年里，第一阶段回避的神经基础-巴甫洛夫恐惧条件反射-已经被详细阐明。这些信息使我们有可能以新的视角重新审视回避的神经基础。特别是，鉴于我们现在已经详细了解了与厌恶的无条件刺激(US)相关的中性环境刺激通过其变成引起厌恶状态(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，特别是如果在研究巴甫洛夫条件反射的神经基础时使用的相同刺激也用于回避条件反射。这些研究将考察杏仁核对逃避的贡献，杏仁核是恐惧条件反射的关键结构。重点将集中在与恐惧条件反射有关的特定核团在回避获得和执行中的可能作用(特别是外侧核、基底核和中央核)，关键杏仁核的解剖输出(特别是从杏仁基底核到伏隔核的投射)的贡献，回避是否在过度训练后成为杏仁核独立的习惯，如果是的话，其他区域是否接管(特别是背侧纹状体)，最后是个体差异在恐惧和回避中的作用及其在预测成瘾和复发易感性方面的价值。

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.