Reversing Cocaine-induced Neurobehavioral Deficits using a Combination Drug Approach

项目摘要 可卡因成瘾是一种慢性的、复发性的脑部疾病，与大脑的调节失调密切相关。 多巴胺和强啡肽系统，这是导致戒断期间出现的焦虑症的原因 可卡因。此外，在禁欲期间，除了奖励不足外，负面影响依然存在， 高度的压力反应，以及无法感受到快乐--所有这些都会导致复发的高风险。这个 从戒毒到戒毒再到随后的吸毒升级的循环太常见了，即使 针对多巴胺和强啡肽系统的大量治疗药物已经被创造出来，但还没有一个 已被证明有效，并被FDA批准用于治疗可卡因成瘾。由于大脑的严重功能障碍 多巴胺和强啡肽系统，我们建议使用多巴胺转运体和kappa阿片受体作为 可卡因成瘾治疗药物开发中可能的细胞靶点。我们最重要的是 假说是将一种多巴胺释放剂和一种kappa阿片类药物结合起来以增强多巴胺能张力。 受体拮抗剂产生抗焦虑和抗抑郁作用，最终降低动力 服用可卡因并使慢性可卡因后的多巴胺和kappa阿片受体系统正常化 在老鼠身上使用。根据我们的初步数据显示，将两种靶向药物组合的结果令人振奋 多巴胺和强啡肽系统，我们建议追求以下具体目标：(1)评估 芬甲肼和LY2444296单独或联合使用都会降低服用动机 可卡因；以及(2)评估芬美曲津和LY2444296单独或联合使用是否会 逆转多巴胺和kappa阿片受体系统的长期失调。总的来说，我们的 拟议的研究使用一种联合治疗方法，其中多巴胺释放剂苯美曲津和 Kappa阿片受体拮抗剂LY2444296可以强调每种单独药物的有益效果， 在慢性可卡因暴露后，靶向两个调节失调的神经递质系统的优势，在一个 可卡因自身给药大鼠模型。这些研究有可能揭示潜在的细胞相互作用。 可以作为治疗可卡因使用障碍的靶点。

Project Summary Cocaine addiction is a chronic, relapsing brain disease that is intimately associated with dysregulations of the dopamine and dynorphin systems, which contributes to the dysphoric syndrome seen during withdrawal from cocaine. Furthermore, during abstinence, a negative affect persists, in addition to a reward deficiency, heightened stress response, and an inability to feel pleasure—all contributing to a high risk of relapse. The cycle from abstinence to withdrawal to subsequent escalation of drug use is far too common, and even though ample therapeutics targeted at the dopamine and dynorphin systems have been created, none have yet been proven effective and approved by the FDA to treat cocaine addiction. Due to the profound dysfunction of the dopamine and dynorphin systems, we propose to use the dopamine transporter and kappa opioid receptor as possible cellular targets in the development of therapeutics for cocaine addiction. Our overarching hypothesis is to combine a dopamine releaser to enhance dopaminergic tone and a kappa opioid receptor antagonist to produce anxiolytic and antidepressant effects, ultimately to reduce motivation to take cocaine and normalize the dopamine and kappa opioid receptor systems after chronic cocaine use in rats. Guided by our preliminary data showing promising results for combining two drugs that target the dopamine and dynorphin systems, we propose to pursue the following specific aims: (1) To assess whether phenmetrazine and LY2444296, both individually and in combination, will reduce the motivation to take cocaine; and (2) To assess whether phenmetrazine and LY2444296, both individually and in combination, will reverse long-term dysregulations in the dopamine and kappa opioid receptor systems. Collectively, our proposed studies use a combination therapy approach, in which the dopamine releaser phenmetrazine and the kappa opioid receptor antagonist LY2444296 may accentuate the beneficial effects of each individual drug, with the advantage of targeting two dysregulated neurotransmitter systems post-chronic cocaine exposure, in a cocaine self-administration rat model. These studies have the potential to uncover potential cellular interactions that can be targeted for treatment of cocaine use disorder.