Interactions of Ethanol & Cocaine Self-Administration in Monkeys

项目摘要 可卡因滥用仍然是一个严重的公共卫生问题，目前还没有广泛有用的方法 药物疗法。已经产生了许多尚未转化为成功的临床前线索 治疗可卡因依赖的药物。这一失败的原因之一可能是，尽管高达90%的可卡因 滥用者还滥用酒精，药物开发过程(临床前动物实验和 对推定药物的早期临床测试)已经在没有接触酒精的受试者中进行。什么 几乎没有关于可卡因/乙醇相互作用的数据表明，这可能代表着一个重要的 令人困惑；乙醇可以增强可卡因对动物和人类的某些影响，并减弱其他影响。 此外，最近的临床试验表明，有酒精依赖史会降低 减少可卡因使用的药物。拟议的研究旨在确定长期的乙醇 在非人类灵长类动物模型中，饮酒改变了可卡因滥用相关的影响，反之亦然。首先，我们将 确定之前的酒精暴露是否会改变可卡因自身的获得和维持(6个月) 行政管理。使用正电子发射断层扫描(PET)的平行脑成像研究将表征 自我给予乙醇、可卡因或其组合改变了大脑中类D2和D3的可获得性 多巴胺受体，与可卡因和酒精滥用有关，并被认为 作为药物治疗发展的靶点。然后我们将检查这些脑成像措施是否 与减少可卡因使用的潜在药物疗法的能力相关。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记物 为了治疗的有效性。最后，自我注射可卡因对随后的酒精自我释放的影响 行政管理将被确定。综上所述，这些研究将提供新的可翻译数据，描述 乙醇和可卡因对彼此滥用相关影响的影响，以及通过准确描述如何 这些药物的联合使用改变了DA受体，将为指导治疗提供新的信息 为同时滥用酒精的绝大多数可卡因使用者做出的决定。

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.