Interactions of Ethanol & Cocaine Self-Administration in Monkeys

项目摘要 可卡因滥用仍然是一个重大的公共卫生问题， 药物治疗已经产生了许多尚未转化为成功的临床前电极导线 治疗可卡因依赖的药物这种失败的一个原因可能是，尽管高达90%的可卡因 滥用者也滥用酒精，药物开发过程（临床前动物实验和 推定药物的早期临床试验）在没有暴露于酒精的受试者中进行。什么 关于可卡因/乙醇相互作用的少量数据表明，这可能代表了一个重要的 混淆;乙醇可以增强可卡因在动物和人类中的某些作用，并减弱其他作用。 此外，最近的临床试验表明，酒精依赖史可以降低 减少可卡因使用的药物。拟议的研究旨在确定长期乙醇 在非人类灵长类动物模型中，饮酒改变了可卡因的滥用相关效应，反之亦然。一是 确定先前的乙醇暴露是否改变可卡因自身的获得和维持（6个月）， 局使用正电子发射断层扫描（PET）的平行脑成像研究将描述如何 乙醇、可卡因或其组合的自我给药改变了脑D2样和D3样的可用性， 多巴胺受体与可卡因和酒精滥用有关， 作为药物治疗发展的目标。然后我们将研究这些脑成像测量 与潜在药物疗法减少可卡因使用的能力相关。重要关系 将表明这些措施可以被医生用作行为表型的生物标志物， 治疗的有效性。最后，自我管理的可卡因对随后的乙醇自我- 行政将决定。总之，这些研究将提供新的可翻译数据， 乙醇和可卡因对彼此滥用相关效应的影响， 联合使用这些药物改变DA受体，将提供新的信息，以帮助指导治疗 大多数可卡因使用者同时滥用酒精。

Project Summary Cocaine abuse remains a significant public health problem for which there are no widely useful pharmacotherapies. Many preclinical leads have been generated that have not translated into successful medications for cocaine dependence. One reason for this failure may be that, although up to 90% of cocaine abusers also abuse alcohol, the medications development process (both preclinical animal experiments and early clinical testing of putative medications) has taken place in subjects with no exposure to alcohol. What little data that exists regarding cocaine/ethanol interactions suggests that this may represent a significant confound; ethanol can enhance some effects of cocaine in animals and humans and attenuate others. Moreover, recent clinical trials have shown that a history of alcohol dependence can reduce the ability of medications to decrease cocaine use. The proposed studies are designed to determine how long-term ethanol drinking alters the abuse-related effects of cocaine and vice versa in nonhuman primate models. First, we will determine whether prior ethanol exposure alters acquisition and maintenance (6 months) of cocaine self- administration. Parallel brain imaging studies using positron emission tomography (PET) will characterize how self-administration of ethanol, cocaine or the combination changes the availability of brain D2-like and D3 dopamine receptors, which have been implicated in both cocaine and ethanol abuse and have been suggested as targets for pharmacotherapy development. We will then examine whether these brain imaging measures correlate with the ability of potential pharmacotherapies to decrease cocaine use. Significant relationships would indicate that such measures could be used by physicians as biomarkers for behavioral phenotypes and for treatment effectiveness. Finally, the effects of self-administered cocaine on subsequent ethanol self- administration will be determined. Taken together, these studies will provide novel translatable data describing the effects of ethanol and cocaine on each other's abuse-related effects and, by characterizing precisely how combined use of these drugs alters DA receptors, will provide novel information to help guide treatment decisions for the large majority of cocaine users who concurrently abuse alcohol.