Cocaine-induced Changes of Mesocorticolimbic Circuitry and Drug-seeking Behavior

描述（由申请人提供）：可卡因依赖是一种严重的健康问题，具有重大的医学和社会影响。在开发可卡因成瘾的有效治疗方法方面进展甚微，戒断者的复吸率仍然很高。在过去几年中，已经报道了压力在成瘾的发展和持续中的关键作用。压力是最常见的药物滥用诱因之一，也是复吸的主要原因之一。然而，压力对成瘾过程产生如此强大影响的机制尚不清楚。复发的动物模型已经证明，压力和药物滥用对大脑中脑多巴胺能系统的影响有很大的相似性，这是一种最常见的与开始吸毒和发展到成瘾晚期有关的途径。暴露于滥用药物会使大脑的多巴胺能系统对压力暴露更敏感，并表明多巴胺神经元传入调节的神经可塑性可能是压力对成瘾个体行为施加控制的机制。然而，参与这种调节的传入神经，以及它们在成瘾发展过程中所经历的变化，还有待确定。目前的建议旨在精确地定义参与应激诱导的恢复的神经回路，确定多巴胺系统的传入调节的改变，并研究这些系统如何影响复发动物模型中的药物寻求行为。该提案所包含的技术培训将为更长期的多学科调查奠定基础，以了解压力和精神兴奋剂暴露如何相互作用，以促进寻求药物的行为。到目前为止，我的训练使我具备了启动此类调查所需的行为和电生理技能。目前的职业发展建议将扩展我以前的培训，并允许这些技术在成瘾领域的重大问题的新应用。此外，我将发展创新技术的经验，包括病毒道追踪和光遗传学，这将使我具备必要的技能，建立一个研究计划，利用综合多学科的方法来解决成瘾和动机行为研究中非常重要的问题。在这个建议和未来的研究中所研究的问题将促进我们对成瘾中压力作用的理解，并促进成功治疗成瘾的方法。 公共卫生相关性：戒毒后复吸是成功治疗精神兴奋剂成瘾的主要挑战之一，在全世界造成严重的健康和社会后果。压力暴露可以通过触发药物渴望和促进复发的可能性来增加精神兴奋剂成瘾的严重性和持续时间。更好地理解在复发过程中大脑的压力和奖励系统如何相互作用，将促进精神兴奋剂成瘾新治疗方法的发展。拟议的研究将使用一种创新的多学科方法来了解这些系统是如何在解剖学，电生理学和行为水平上改变的。

DESCRIPTION (provided by applicant): Cocaine dependence is a severe health problem with significant medical and societal impact. Minimal progress has been made towards developing effective treatments for cocaine addiction, and relapse rates for abstinent users remain high. A critical role for stress in the development and persistence of addiction has been reported over the past several years. Stress is one of the most commonly reported precipitants of drug abuse and is one of the major causes of relapse to drug-taking. However, the mechanisms by which stress exerts such a powerful influence over addictive processes are not well understood. Animal models of relapse have demonstrated strong similarities in the effects of stress and drugs of abuse on the midbrain dopaminergic system of the brain, a pathway most commonly implicated in the initiation of drug-taking and the progression to advanced stages of addiction. Exposure to drugs of abuse renders the dopaminergic systems of the brain more responsive to stress exposure, and indicates that neuroplasticity in the afferent regulation of dopamine neurons may be a mechanism by which stress comes to exert control over behavior in the addicted individual. However, the afferents involved in such regulation, and the changes that they undergo during the development of addiction, have yet to be identified. The current proposal seeks to precisely define the neurocircuitry involved in stress-induced reinstatement, identify alterations in the afferent regulation of the dopamine system, and investigate how such systems may influence drug seeking behavior in an animal model of relapse. The technical training encompassed by this proposal will build a foundation for more long-term multidisciplinary investigations into how stress and psychostimulant exposure interact to promote drug-seeking behavior. My training thus far has equipped me with the behavioral and electrophysiological skills necessary to initiate such investigations. The present career development proposal will extend my previous training and allow novel application of these techniques to significant issues in the field of addiction. Further, I will develop experience in innovative techniques, including viral tract tracing and optogenetics, which will give me the skill necessary to establish a research program that utilizes a comprehensive multidisciplinary approach to address questions of great importance in the study of addiction and motivated behavior. Issues examined in this proposal and in future studies will advance our understanding of the role of stress in addiction, as well as facilitate approaches for the successful treatment o addiction. PUBLIC HEALTH RELEVANCE: Relapse to drug use following abstinence is one of the main challenges to the successful treatment of psychostimulant addiction, which has significant health and social consequences throughout the world. Stress exposure can increase the severity and duration of psychostimulant addiction by triggering drug craving and contributing to the likelihood for relapse. A greater understanding of how the stress and reward systems of the brain interact during the process of relapse will enhance the development of novel treatment approaches to psychostimulant addiction. The proposed studies will use an innovative multidisciplinary approach to understand how these systems are altered at the anatomical, electrophysiological, and behavioral levels.