Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.