Repurposing drugs in mixtures to treat drug abuse

总结/摘要 兴奋剂滥用是一个严重的公共卫生问题，具有难以估量的医疗，社会和经济影响 国际吧尽管对药物滥用的神经生物学进行了数十年的研究， 兴奋剂滥用的药物治疗。一种减少获得候选药物所需时间的策略 进入临床是重新使用药物，已经被FDA批准用于其他适应症，治疗兴奋剂滥用， 提高药物治疗效果的一种策略是将其与第二种药物联合给药， 具有互补作用机制的药物。我们和其他人已经证明，阻断 DA（丁螺环酮[Buspar®]; DA D2样[D2、D3和D4]受体拮抗剂，FDA批准用于治疗焦虑症）或 调节DA传递（氯卡色林[Belviq®]; 5-羟色胺[5-HT]2C受体激动剂，FDA批准用于治疗 肥胖症）减弱兴奋剂如可卡因在动物中的增强和/或复发相关作用。基于 在对雄性和雌性恒河猴进行的非常有希望的初步研究中，我们假设联合治疗 包括靶向DA的前（氯卡色林）和后（丁螺环酮）突触调节剂的固定剂量的药物 神经传递将具有治疗效果（例如，减少药物摄入），其效果大于 或者单独使用药物（即，超加性相互作用）。我们的初步数据支持这一假设，并表明， 将丁螺环酮与氯卡色林组合将产生高度可转化的和新颖的治疗兴奋剂滥用的方法。 目标1下的研究检验了以下假设：靶向前（氯卡色林）和后（丁螺环酮）的药物混合物 DA神经传递的突触调节剂导致增强（进行性）的超累加抑制， 比率和可卡因食物选择）和可卡因的复发相关（恢复）效应，这些效应 作为性别的函数而不同（例如，雌性对丁螺环酮单独不太敏感，但对 氯卡色林：丁螺环酮混合物）。目的2：验证以下假设： 当在混合物中组合时，氯卡色林和丁螺环酮不改变，并且氯卡色林和丁螺环酮的混合物在混合物中不改变。 丁螺环酮不会加重，可能会减弱可卡因的心血管作用;预期不会产生这些作用 性别的差异拟议的研究建立在令人信服的初步数据和测试的小说 假设包括固定剂量的FDA批准的靶向突触前神经元的药物的组合疗法 （5-HT 2C受体;氯卡色林）和突触后（DA D3受体;丁螺环酮）DA调节剂 神经传递在减少增强和复发相关效应方面更有效和/或更有效。 可卡因比基于单独的任一种药物的效果所预期的要多（即，超加性相互作用）， 而不会加重可卡因对心血管的影响。这些研究不仅提供了新的 关于靶向5-HT 2C和DA D3受体的药物混合物的作用的信息（4年内），但由于 氯卡色林和丁螺环酮已经被FDA批准用于人类，这些结果将是高度 可移植到诊所，大大减少了确定有效性所需的时间和成本， 氯卡色林和丁螺环酮的混合物来治疗可卡因滥用。

SUMMARY/ABSTRACT Stimulant abuse is a serious public health problem with untold medical, societal, and economic impact worldwide. Despite decades of research into the neurobiology of drug abuse, there are no FDA-approved pharmacotherapies for stimulant abuse. One strategy to reduce the time required to get candidate medications into the clinic is to repurpose drugs, already approved by the FDA for other indications, to treat stimulant abuse, and one strategy to improve the therapeutic effectiveness of a drug is to administer it in combination with second drug with a complimentary mechanism of action. We and others have shown that drugs that block the effects of DA (buspirone [Buspar®]; a DA D2-like [D2, D3, & D4] receptor antagonist, FDA-approved for treating anxiety) or modulate DA transmission (lorcaserin [Belviq®]; a serotonin [5-HT]2C receptor agonist, FDA-approved for treating obesity) attenuate the reinforcing and/or relapse-related effects of stimulants such as cocaine in animals. Based on very promising pilot studies in male and female rhesus monkeys, we hypothesize that a combination therapy comprising fixed-doses of drugs that target both pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission will have a therapeutic effect (e.g., decrease in drug-taking) that is greater than the effect of either drug alone (i.e., supra-additive interaction). Our preliminary data support this hypothesis and suggest that combining buspirone with lorcaserin will yield a highly translatable and novel approach to treat stimulant abuse. Studies under Aim 1 test the hypotheses that mixtures of drugs targeting pre- (lorcaserin) and post- (buspirone) synaptic regulators of DA neurotransmission result in a supra-additive inhibition of the reinforcing (progressive ratio and cocaine-food choice) and relapse-related (reinstatement) effects of cocaine, and that these effects differ as a function of sex (e.g., females being less sensitive to buspirone alone, but more sensitive to lorcaserin:buspirone mixtures). Aim 2 tests the hypotheses that the cardiovascular and locomotor effects of lorcaserin and buspirone are not altered when combined in a mixture, and that mixtures of lorcaserin and buspirone do not exacerbate, and may blunt, the cardiovascular effects of cocaine; these effects are not expected to differ as a function of sex. The proposed studies build on compelling preliminary data and test the novel hypothesis that a combination therapy comprising fixed-doses of FDA-approved drugs that target pre-synaptic (5-HT2C receptors; lorcaserin) and post-synaptic (DA D3 receptors; buspirone) regulators of DA neurotransmission are more potent and/or effective at reducing the reinforcing and relapse-related effects of cocaine than would be expected based on the effect of either drug alone (i.e., a supra-additive interaction), without also exacerbating the cardiovascular effects of cocaine. These studies will not only provide new information (within 4 years) about the effects of drug mixtures targeting 5-HT2C and DA D3 receptors, but because lorcaserin and buspirone are already approved by the FDA for use in humans, these results will be highly translatable to the clinic, significantly reducing the time and cost required to determine the effectiveness of mixtures of lorcaserin and buspirone to treat cocaine abuse.