Activation of KORs with the agonist U50,488 has been reported to both block and potentiate ethanol-induced conditioned place preference (CPP). While these studies have employed different rodent species and strains, it appears that dose and timing of U50,488 administration may be the most critical factors in determining the direction of study outcomes. In two studies in which U50,488 (0.3 – 3 mg/kg) was administered shortly (i.e., 0 – 10 min) before ethanol injections during the conditioning phase, subjects spent less time on the ethanol-paired side during the CPP test session (Logrip et al., 2009; Matsuzawa et al., 1999). That is, under these experimental conditions, the KOR agonist attenuated ethanol-induced CPP. In contrast, opposite results were observed in another study that examined a higher dose of U50,488 (10 mg/kg) with a longer pretreatment time (90 min before ethanol), suggesting that under these conditions, KOR activation potentiated expression of ethanol-induced CPP (Sperling et al., 2010). At present, it is unclear how dose or timing (or both variables) of a KOR agonist interacts with ethanol to produce opposite effects on the conditioned rewarding effects of ethanol. Additional studies focused on underlying mechanisms may help clarify this issue.
