Dose and timing variables appear to be important factors that define how KOR pharmacological agents influence ethanol effects, particularly conditioned ethanol reward. For example, the KOR agonist U50,488 has been shown to both block and potentiate ethanol-induced CPP. In general, studies showing that U50,488 enhanced ethanol CPP used doses of the agonist that were shown in other studies to produce a conditioned place aversion when given alone (McLaughlin et al., 2006). Studies demonstrating reduced ethanol CPP used lower doses of U50,488 that did not produce a conditioned aversion effect alone (Logrip et al., 2009). In addition to U50,488 dose, the relative timing of KOR activation in relation to ethanol administration appears to have an important influence on these study outcomes. That is, studies using a short pretreatment time (0–10 minutes before conditioning) report that U50,488 blocks ethanol-induced CPP (Logrip et al., 2009; Matsuzawa et al., 1999), whereas studies with a longer pretreatment time (90 minutes) report potentiation of ethanol CPP (Sperling et al., 2010). Interestingly, U50,488 alone elicited a significant conditioned place aversion when administered 15 minutes prior to conditioning
