Neural Mechanisms of Cocaine Addiction

描述(由申请者提供)：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，这可能是目前治疗可卡因成瘾面临的最具挑战性的问题。暴露在可卡因条件刺激(CSS)中会引发无法控制的动机，即使在长期戒酒后也会驱动寻求可卡因的行为，最终导致复发。虽然在利用灭绝/恢复模型来理解CS如何作用于大脑回路以维持或加强已经启动的可卡因寻找行为方面取得了快速进展，但由于缺乏合适的动物模型，在启动和驱动可卡因寻找行为中起关键作用的可卡因CS的神经生物学机制的研究进展受到阻碍。这一建议旨在促进我们对可卡因的条件性刺激--可卡因的激励效应--预测可卡因复吸-寻找行为的条件性刺激--的神经机制的理解。越来越多的证据表明，大脑皮层多巴胺(DA)环路可能在这些效应中起关键作用。我们假设可卡因刺激的兴奋效应主要依赖于可卡因刺激对中皮质DA环路的激活，而且这种激活依赖于谷氨酸输入腹侧被盖区和DA输入前额叶(PFC)。目前研究药物CS的激励-动机效应的一个障碍是，目前的动物模型不能区分CS的条件性激励-动机效应和其他条件性效应，如条件性增强效应和自动反应诱发效应。为了填补这一空白，本文提出了一种新的基于巴甫洛夫迁移范式的动物模型。使用这个模型，我们建议用电生理学和药理学的综合研究来检验我们的假设，这些研究通过预测可卡因的CS恢复了可卡因寻找行为。这项拟议研究的一个显著特点是，在CS诱导的恢复过程中，动物在进行可卡因寻找行为时，将监测PFC中的神经元活动。同时监测神经元的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，通过研究直接显微注射到大脑皮层DA环内对受体特异性拮抗剂恢复的影响，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亟需的动物模型，还将阐明可卡因预测CS的条件性激励-激励效应背后的神经底物、受体系统和神经机制。这些信息最终将有助于新的戒毒疗法的开发。吸毒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。目前对这种疾病的治疗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以防止或最大限度地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.