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（CS）可以唤起难以控制的动机，即使在长时间的禁欲，以驱动可卡因寻求行为，并最终复吸。尽管通过使用消退/恢复模型，在理解CS如何作用于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，但由于缺乏合适的动物模型，在理解可卡因CS的激励-动机性质的神经生物学机制方面的进展受到阻碍，可卡因CS在启动和驱动可卡因寻求行为中起着关键作用。该建议旨在促进我们对可卡因预测CS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）电路可能是至关重要的参与这些影响。我们假设，可卡因CSs的激励动机的影响，关键取决于激活中皮层DA电路的CSs，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CS的激励-动机效应的一个障碍是现有的动物模型不能区分CS的条件激励-动机效应和其他条件效应，如条件强化效应和自动反应-诱发效应。为了填补这一空白，提出了一种新的动物模型的基础上巴甫洛夫工具转移范式。使用这个模型，我们建议测试我们的假设与可卡因预测CS恢复可卡因寻求行为的电生理学和药理学的综合研究。拟议研究的一个显著特征是，在CS诱导的恢复期间，当动物执行可卡因寻求行为时，将监测PFC中的神经元活动。同时监测神经元活动和行为为研究行为的神经机制提供了有力的工具。此外，通过研究受体特异性拮抗剂直接显微注射到中皮层DA电路的恢复的影响，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，但将揭示的神经基板，受体系统，和神经元机制的可卡因预测CS的条件激励动机的影响。药物成瘾是一种慢性脑部疾病，给吸毒者、家庭和社会带来沉重的负担。目前治疗这种疾病面临的一个主要挑战是，即使在长期禁欲之后，复发率也很高。这项提案旨在了解复发的基本大脑机制，因此，将提供有关我们如何操纵大脑过程以预防或尽量减少复发的重要信息。

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.