Synthesis of the literature reviewed in this paper indicates that a history of ethanol exposure plays an important role in modifying how KOR pharmacological agents influence motivational effects of ethanol. Much of this work has focused on effects of KOR agonists and antagonists on ethanol self-administration. Specifically, many studies have shown that KOR antagonists are especially effective in reducing elevated ethanol intake in dependent animals with little or no effect on more modest ethanol consumption in non-dependent animals (Kissler and Walker, 2016; Rose et al., 2016; Walker and Koob, 2008; Walker et al., 2012). This falls in line with the notion that while DYN/KOR activity may not play a significant role in initially regulating ethanol consumption, chronic ethanol exposure engages the DYN/KOR system in a manner that mediates and/or promotes increased motivation to drink (see Koob, 2013; Tejeda et al., 2012). Adaptations in DYN/KOR signaling following chronic ethanol exposure also have been shown to contribute to negative affect and dysphoria associated with withdrawal, effects that may fuel desire to engage in excessive levels of ethanol intake (Kissler et al., 2014; Kissler and Walker, 2016; Rose et al., 2016).
