Striatal mechanisms of relapse to cocaine seeking

描述（由申请人提供）：戒断后复吸是药物依赖长期治疗的重大障碍。先前与药物使用有关的环境刺激或背景可能引发强迫性药物寻求和药物服用行为的复发。在大鼠慢性自我给药后，恢复对药物相关条件提示的反应，无论是离散的还是上下文的。虽然条件提示的作用被认为是复发的一个因素，但直到最近才对各种滥用药物复发的基本神经回路进行了详细的探索。使用复发的消退/恢复模型，基底外侧杏仁核复合体的作用已被证明在驱动复发的药物线索关联的获取、巩固和表达中至关重要。此外，条件提示恢复的回路涉及一个包括前额叶皮层和伏隔核的离散亚区在内的脑核网络。虽然消退/恢复范式允许研究者分离出诱发复发的刺激的特定特征，但人类成瘾者在停止使用药物后通常不会接受明确的消退训练。我们实验室最近的研究表明，戒断药物和药物配对环境后复发的神经回路的激活与外显消失训练后的神经回路的激活是唯一不同的。这些发现暗示了背外侧尾状壳核（dlCPu）在戒断后介导复发中的重要作用。在这一竞争性更新应用中，研究人员提出了一种全球假设，即dlCPu的神经适应性变化是戒断慢性可卡因自我给药后习惯性寻求药物的基础。具体来说，我们假设dlCPu是习惯学习的关键调节器，在戒断后复发期间驱动强迫性药物寻求。这些变化被假设涉及dlCPu神经元活动的变化，表现为特异性多巴胺和谷氨酸受体介导的细胞信号级联的变化以及复发期间dlCPu中多巴胺和谷氨酸释放的增加。这些实验提供了一种综合的方法，采用行为、分子生物学和神经化学技术，旨在了解慢性可卡因自我给药期间和之后产生的长期条件关联的神经元基础。从这个项目获得的资料将为开发治疗可卡因依赖的抗复发药物以及其他滥用药物提供方向。

DESCRIPTION (provided by applicant): Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug dependence. Environmental stimuli or contexts previously associated with drug use can initiate relapse to compulsive drug-seeking and drug-taking behaviors. Reinstatement of responding for drug-associated conditioned cues, both discrete and contextual, following chronic drug self-administration has been demonstrated in rats. Although the role of conditioned cues is well recognized as a factor in relapse, only recently has the fundamental neural circuitry of relapse to various drugs of abuse been explored in detail. Using an extinction/reinstatement model of relapse, the role of the basolateral amygdala complex has been shown to be critical in the acquisition, consolidation, and expression of drug-cue associations that drive relapse. Furthermore, the circuitry of conditioned-cued reinstatement engages a network of brain nuclei that include discrete subregions of the prefrontal cortex and nucleus accumbens. Although extinction/reinstatement paradigms allow investigators to isolate specific features of stimuli that elicit relapse, human addicts generally do not undergo explicit extinction training upon cessation of drug use. Recent studies from our laboratory suggest that activation of the neural circuitry underlying relapse to drug-seeking after abstinence from the drug and the drug-paired environment is uniquely different from that engaged following explicit extinction training. These findings have implicated a significant role of the dorsolateral caudate-putamen (dlCPu) in mediating relapse following abstinence. In this competing renewal application, studies are proposed to test the global hypothesis that neuroadaptive changes in the dlCPu underlie habitual drug-seeking following abstinence from chronic cocaine self-administration. Specifically, we hypothesize that the dlCPu is a key regulator of habit learning that drives compulsive drug-seeking during relapse after abstinence. These changes are hypothesized to involve a change in neuronal activity of the dlCPu as manifested by changes in specific dopamine and glutamate receptor-mediated cell signaling cascades and increased dopamine and glutamate release in the dlCPu during relapse. These experiments provide an integrated approach employing behavioral, molecular biological, and neurochemical techniques aimed at understanding the neuronal bases of long-term conditioned associations produced during and after chronic cocaine self-administration. Information gained from this project will provide direction for development of anti-relapse medications for the treatment of cocaine dependence, as well as other drugs of abuse.