Interestingly, effects of KOR agonists on ethanol consumption appear to be less selective. For example, the KOR agonist U50,488 was reported to produce a similar increase in ethanol consumption in both dependent and non-dependent mice (Anderson et al., 2016), suggesting similar sensitivity to direct KOR activation in increasing ethanol intake regardless of a history of ethanol exposure. In another study, systemic administration of U50,488 elevated ethanol consumption in non-dependent mice (Rose et al., 2016). Thus, in contrast to KOR antagonism selectively reducing ethanol consumption in dependent animals, these results suggest that systemic administration of a KOR agonist effectively increases ethanol drinking in both dependent and non-dependent subjects. Specific mechanisms underlying this effect (e.g., dependence-related adaptations in DYN synthesis/release and/or changes in KOR expression/function) have yet to be fully elucidated.
