Pharmacogenetic approaches to the treatment of alcohol addiction

Key Points Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine. The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use. Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus. Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone. Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence. Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use. Genetic variation that influences the functional activity of the CRF system has been