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

描述(申请人提供)：可卡因依赖是一个严重的健康问题，具有重大的医学和社会影响。在开发有效的可卡因成瘾治疗方法方面进展甚微，戒毒者的复吸率仍然很高。在过去的几年里，压力在成瘾的发展和持续中起到了关键作用。压力是最常见的药物滥用诱因之一，也是吸毒复发的主要原因之一。然而，压力对成瘾过程产生如此强大影响的机制还不是很清楚。复吸的动物模型已经证明，压力和滥用药物对大脑中脑多巴胺系统的影响具有很强的相似性，这是一条最常见的与吸毒开始和发展到成瘾晚期有关的途径。暴露在滥用药物中会使大脑的多巴胺能系统对压力更敏感，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者行为施加控制的一种机制。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。目前的提案试图准确定义参与应激诱导恢复的神经回路，确定多巴胺系统传入调节的变化，并调查这种系统可能如何影响复发动物模型的药物寻求行为。该提案包含的技术培训将为更长期的多学科调查奠定基础，调查压力和精神刺激剂暴露如何相互作用，促进药物寻找行为。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。目前的职业发展提案将扩展我以前的培训，并允许在成瘾领域的重大问题上以新的方式应用这些技术。此外，我将积累创新技术方面的经验，包括病毒道追踪和光遗传学，这将使我拥有必要的技能，以建立一个研究计划，利用综合的多学科方法来解决成瘾和动机行为研究中的重要问题。在这项建议和未来的研究中所研究的问题将促进我们对压力在成瘾中的作用的理解，并促进成功治疗成瘾的方法。

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.