In contrast, KOR agonists are reported to similarly increase ethanol consumption in both dependent and non-dependent animals (Anderson et al., 2016). Thus, direct activation of KORs can mimic elevated ethanol consumption observed following chronic ethanol exposure. Interestingly, although KOR agonists appear to exhibit similar efficacy in increasing ethanol consumption in dependent and non-dependent animals, chronic ethanol exposure has been shown to enhance sensitivity to KOR-induced decreases in accumbal dopamine transmission (Karkhanis et al., 2016a; Rose et al., 2016). This upregulated KOR function in the nucleus accumbens (reducing dopamine tone) along with increased KOR function in the central amygdala are thought to underlie ethanol withdrawal-related behaviors reflective of dysphoria and, in turn, increased motivation to drink (Kissler et al., 2014; Rose et al., 2016). Further studies are needed to fully characterize how chronic ethanol exposure alters functional activity of the DYN/KOR system and how such adaptations relate to relevant behavioral effects.
