Striatal mechanisms of relapse to cocaine seeking

描述(由申请人提供)：戒毒后复发是长期治疗药物依赖的一个重大障碍。以前与药物使用有关的环境刺激或背景可能会引发强迫性寻求毒品和吸毒行为的复发。在长期给药后，大鼠对药物相关的条件性线索的反应恢复，包括离散的和上下文的，已经在大鼠中得到证实。尽管条件性线索的作用被公认为是复发的一个因素，但直到最近，人们才详细研究了各种滥用药物复发的基本神经回路。利用复发的消退/恢复模型，杏仁核基底外侧复合体的作用已被证明在驱动复发的药物-线索联系的获得、巩固和表达中起关键作用。此外，条件性提示恢复的回路涉及一个大脑核团网络，其中包括前额叶皮质和伏隔核的离散亚区。尽管戒毒/复吸范式允许研究人员分离出引起复发的刺激的特定特征，但人类吸毒者通常不会在停止使用毒品后接受明确的戒毒训练。我们实验室最近的研究表明，戒毒后复吸的神经回路的激活和药物配对环境与明确的戒毒训练后的激活是独特的不同。这些发现表明，背外侧尾壳核(DlCPu)在调节戒断后复发方面起着重要作用。在这种相互竞争的更新应用中，有人建议进行研究，以检验全球假说，即dlcpu的神经适应性变化是慢性可卡因自我给药戒断后习惯性寻求药物的基础。具体地说，我们假设dlcpu是习惯学习的关键调节器，在戒酒后复发期间驱动强制寻求药物。这些变化被认为涉及dlcpu神经元活性的变化，表现为特定的多巴胺和谷氨酸受体介导的细胞信号级联反应的变化，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，利用行为、分子生物学和神经化学技术，旨在了解在长期服用可卡因期间和之后产生的长期条件性联系的神经元基础。从该项目获得的信息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.