Reversing Cocaine-induced Neurobehavioral Deficits using a Combination Drug Approach

项目摘要 可卡因成瘾是一种慢性复发性脑部疾病， 多巴胺和强啡肽系统，这有助于在戒断期间观察到的烦躁综合征。 可卡因此外，在禁欲期间，除了奖励不足之外，负面影响仍然存在， 高度的压力反应，以及无法感到快乐--所有这些都导致了复发的高风险。的 从禁欲到戒断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充足疗法已经被创造出来，但还没有一种被 被FDA证实有效并批准用于治疗可卡因成瘾。由于严重的功能障碍， 多巴胺和强啡肽系统，我们建议使用多巴胺转运蛋白和κ阿片受体， 可能的细胞靶点在可卡因成瘾治疗的发展。我们的总体 假设是将增强多巴胺能张力多巴胺抑制剂和κ阿片样物质联合收割机组合 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κ阿片受体系统正常化 在大鼠中使用。在我们的初步数据的指导下，显示了联合两种靶向药物的有希望的结果。 多巴胺和强啡肽系统，我们建议追求以下具体目标：（1）评估是否 苯甲曲嗪和LY 2444296，无论是单独使用还是联合使用，都会降低服用的动机。 可卡因;和（2）评估苯甲曲嗪和LY 2444296单独或联合使用是否会 逆转多巴胺和κ阿片受体系统的长期失调。总体而言，我们 建议的研究使用联合治疗方法，其中多巴胺释放剂苯甲曲嗪和 κ阿片样物质受体拮抗剂LY 2444296可以加强每种药物的有益作用， 由于靶向慢性可卡因暴露后两种失调的神经递质系统的优势， 可卡因自我给药大鼠模型。这些研究有可能揭示潜在的细胞相互作用 可以用于治疗可卡因使用障碍。

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.