RC4 Glutamate-opioid interactions in alcohol drinking behaviors

酒精依赖是一种慢性、复发性疾病，针对这种疾病的药物开发是基于对介导饮酒行为的神经化学过程的系统理解。有大量的证据表明，在酒精奖励过程中，多巴胺能和阿片类系统发挥了作用。在CTNA 1中，我们首次表明，减少饮酒的功效仅在具有积极的酒精中毒家族史（FHP）的饮酒者中观察到，而在具有消极的酒精中毒家族史（FHN）的饮酒者中则没有观察到;有趣的是，这种饮酒的减少伴随着酒精渴望的非常适度的减少，并且对酒精诱导的刺激没有影响。在CTNA 2中，我们使用谷氨酸能剂美金刚进行了类似的检查，并再次观察到仅在FHP中而不是在FHN饮酒者中的效果;有趣的是，美金刚似乎减少了酒精刺激和酒精渴望，对饮酒有适度的影响。这一令人兴奋的证据表明，多巴胺能和阿片类药物可能靶向饮酒所涉及的不同行为过程。酒精依赖重度饮酒者的习惯性酒精使用可能不仅依赖于持续的酒精奖励，还依赖于条件激励过程，如线索诱导的渴望和自动化的动机倾向，这是由不同神经化学过程之间的复杂相互作用介导的，并且可以通过美金刚和纳洛酮进行差异化靶向。在CTNA 3中，我们将进行 “概念验证”I期评价，以检查纳洛酮和美金刚联合治疗对饮酒和酒精奖励的影响，如使用酒精诱导的刺激和渴望测量的，在非寻求治疗、酒精依赖、具有阳性酒精中毒家族史的重度饮酒者中。探索性目的还将评估这些药物对饮酒自动动机倾向的影响，并检查新行为（巴甫洛夫到工具转移任务）和遗传（纹状体富集磷酸盐Fyn激酶）预测因子对治疗反应的影响。

Alcohol dependence is a chronic, relapsing disorder and the development of medications for this disorder has been based on a systematic understanding of the neurochemical processes mediating alcohol drinking behaviors. There is extensive evidence for a role for the glutamatergic and opioidergic systems in alcohol reward processes. In CTNA1 we showed for the first time that the efficacy of in reducing drinking is only observed in drinkers with a positive family history of alcoholism (FHP) and not in those with a negative family history of alcoholism (FHN); interestingly, this reduction in drinking was accompanied by very modest reductions in alcohol craving and no effects on alcohol-induced stimulation. In CTNA2 we conducted a similar examination using the glutatmatergic agent memantine, and again observed effects only in FHP but not in FHN drinkers; interestingly memantine appears to reduce alcohol stimulation and alcohol craving with modest effects on alcohol drinking. This exciting evidence suggests that glutamatergic and opioidergic agents may target different behavioral processes involved in alcohol drinking. Habitual alcohol use in alcohol dependent heavy drinkers may be dependent not just on continued alcohol reward but also on conditioned incentive processes, like cue-induced craving and automated motivational tendencies, which are mediated by complex interactions between different neurochemical processes, and could be targeted differentially by memantine and naltrexone. In CTNA3 we will conduct a "proof of concept" Phase I evaluation to examine the effect of combined treatment with naltrexone and memantine on alcohol drinking and alcohol reward as measured using alcohol-induced stimulation and craving, in non-treatment seeking, alcohol dependent, heavy drinkers with a positive family history of alcoholism. Exploratory aims will also evaluate the influence of these medications on automated motivational tendencies towards alcohol drinking and also examine the influences of novel behavioral (Pavlovian to Instrumental transfer task) and genetic (Striatally enriched phosphates Fyn kinas) predictors on treatment response.