Neural Mechanisms of Cocaine Addiction

描述（由申请人提供）：该项目的长期目标是了解可卡因成瘾的基本大脑机制，特别是复发，这可能是目前可卡因成瘾治疗面临的最具挑战性的问题。暴露于可卡因条件刺激（CSs）可以唤起难以控制的动机，甚至在长时间的戒断之后，驱动可卡因寻求行为并最终复发。尽管通过使用灭绝/恢复模型，在理解CSs如何作用于大脑回路以维持或加强已经启动的可卡因寻求行为方面取得了快速进展，但由于缺乏适当的动物模型，在理解可卡因CSs在启动和驱动可卡因寻求行为中起关键作用的激励-动机特性背后的神经生物学机制方面取得了进展。本研究旨在加深我们对可卡因预测CSs对可卡因寻求行为复发的条件激励-动机效应的神经机制的理解。新出现的证据表明，中皮层多巴胺（DA）回路可能在这些影响中起关键作用。我们假设可卡因CSs的激励-动机效应严重依赖于CSs对中脑皮层DA回路的激活，而且这种激活依赖于谷氨酸输入到腹侧被盖区和DA输入到前额叶皮层（PFC）。研究药物CSs的激励-动机效应的一个障碍是目前的动物模型不能区分CSs的条件激励-动机效应与其他条件效应如条件强化和自动反应诱导效应。为了填补这一空白，本文提出了一种基于巴甫洛夫向工具转移范式的新型动物模型。使用这个模型，我们建议通过可卡因预测CSs恢复可卡因寻求行为的电生理学和药理学综合研究来检验我们的假设。拟议研究的一个显著特征是，当动物在cs诱导的恢复过程中表现出可卡因寻求行为时，将监测PFC的神经元活动。同时监测神经元活动和行为为研究行为的神经元机制提供了有力的工具。此外，通过研究直接微注射受体特异性拮抗剂对中皮层DA回路恢复的影响，我们将确定参与这一过程的分子机制。总之，这些研究不仅将提供一个急需的动物模型，而且将阐明可卡因预测CSs的条件激励-动机效应的神经基质、受体系统和神经元机制。这些信息最终将有助于开发新的抗成瘾疗法。药物成瘾是一种慢性脑部疾病，给吸毒者、家庭和社会带来了沉重的负担。目前这种疾病的治疗面临的一个主要挑战是，即使在长时间的戒断后，复发率也很高。这一建议旨在了解复发的基本大脑机制，因此，将为我们如何操纵大脑过程来预防或减少复发提供重要信息。

DESCRIPTION (provided by applicant): The long-term objective of the project is to understand the basic brain mechanisms underlying cocaine addiction, in particular, relapse which is probably the most challenging issue facing the current treatment of cocaine addiction. Exposure to cocaine-conditioned stimuli (CSs) can evoke unmanageable motivation even after long periods of abstinence to drive cocaine-seeking behavior and ultimately, relapse. Although rapid progress has been made in understanding how the CSs act on the brain circuits to sustain or reinforce already- initiated cocaine-seeking behavior by using extinction/reinstatement models, advances in understanding the neurobiological mechanisms underlying the incentive-motivational property of cocaine CSs, which plays a critical role in initiating and driving cocaine-seeking behavior, are hindered due to lack of appropriate animal models. This proposal aims to advance our understanding on the neural mechanisms underlying the conditioned incentive-motivational effects of cocaine-predicting CSs on relapse to cocaine-seeking behavior. Emerging evidence indicates that the mesocortical dopamine (DA) circuit may be critically involved in these effects. We hypothesize that the incentive-motivational effects of cocaine CSs critically depend upon activation of the mesocortical DA circuit by the CSs and moreover, such activation depends on glutamate input to the ventral tegmental area and DA input to the prefrontal cortex (PFC). One obstacle in studying the incentive- motivational effects of drug CSs is that the current animal models can not differentiate conditioned incentive- motivational effects of CSs from other conditioned effects such as conditioned reinforcing and automatic response-eliciting effects. To fill this gap, a novel animal model is proposed here based on the Pavlovian-to- instrumental transfer paradigm. Using this model we propose to test our hypothesis with integrated studies of electrophysiology and pharmacology of cocaine-seeking behavior reinstated by cocaine-predicting CSs. One distinctive feature of the proposed studies is that neuronal activity in the PFC will be monitored while animals are performing cocaine-seeking behavior during the CS-induced reinstatement. Simultaneous monitoring of neuronal activity and behavior provides a powerful tool to study the neuronal mechanisms of the behavior. In addition, by studying the effects on the reinstatement of receptor-specific antagonists directly microinjected into the mesocortical DA circuit, we will identify the molecular mechanisms involved in this process. Together, these studies will not only provide a much needed animal model but will shed light on the neural substrates, receptor systems, and neuronal mechanisms underlying the conditioned incentive-motivational effects of cocaine-predicting CSs. Such information will ultimately contribute to development of new anti-addiction therapies.Drug addiction is a chronic brain disease which exerts a heavy burden on drug addicts, family, and society. One major challenge facing current treatment of the disease is a high rate of relapse even after long periods of abstinence. This proposal aims to understand the basic brain mechanisms underlying relapse and therefore, will provide important information on how we can manipulate the brain processes to prevent or minimize relapse.