As noted above, KOR antagonists have been reported to significantly reduce elevated ethanol consumption in ethanol dependent animals. In a series of studies, Walker and colleagues have demonstrated that the KOR antagonist nor-BNI reduced escalation of ethanol consumption observed in dependent rats without influencing consumption in non-dependent animals (Walker and Koob, 2008; Walker et al., 2011, Kissler et al., 2014). Similar effects were reported in a recent study involving ethanol dependent mice (Rose et al., 2016). In another study that reported stress-induced enhancement of escalated drinking in dependent mice, the novel short-acting KOR antagonist, LY2444296 (Mitch et al., 2011), was shown to significantly attenuate this effect (Anderson et al., 2016). Taken together, there is converging evidence that pharmacological blockade of KORs reduces escalated drinking associated with dependence. These results appear congruent with previously noted evidence that ethanol dependence, particularly induced by chronic ethanol vapor inhalation, up-regulates the DYN/KOR system (e.g., Kissler et al., 2014).
