2013). Furthermore, JDTic-induced suppression of spontaneous recovery of alcohol responding can occur up to 14 days after JDTic treatment (Deehan et al. 2012). The reasons for these discrepancies in the time course of the antagonism of KOR and the suppressive actions of nor-BNI and JDTic on drug- or alcohol-related behaviors are not clear. One potential explanation is that at the 2 h post nor-BNI injection time point we use, the early-appearing MOR antagonist Inhibitors,research,lifescience,medical properties of nor-BNI may be

still present (Endoh et al. 1992). This is unlikely to be the case, as the MOR blockade induced by nor-BNI occurs in the first hour after administration. Inhibitors,research,lifescience,medical By 2 h post injection, selectivity for KOR is 100-fold higher than for MOR (Endoh et al. 1992). Furthermore, we saw a complete blockade by nor-BNI of the reinstatement induced

by the highly selective KOR agonist U50,488 at 2, but not 24 h. Another possibility is that time-dependent effects are highly specific to the outcomes measured. For example, most of the data on the long-lasting effects of nor-BNI come from BIIB057 studies measuring pain, which is mediated by quite different systems than are motivated behaviors. Arguing against this idea, however, are recent findings Inhibitors,research,lifescience,medical that nor-BNI blocked yohimbine-induced reinstatement of heroin seeking 24 h after administration (Zhou et al. 2013), and our observation that nor-BNI was still able to significantly attenuate yohimbine-induced reinstatement of nicotine seeking 24 h after administration (Grella, Funk, Coen, Li, Lê, in revision). KOR and stress-induced Inhibitors,research,lifescience,medical alcohol seeking The selective KOR antagonist, nor-BNI significantly attenuated reinstatement of alcohol

seeking induced by the pharmacological stressor yohimbine. These results a support those from studies on the role of KOR and stress in the expression of CPP to other drugs. Nor- BNI blocks stress- and U50,488-induced potentiation of CPP to cocaine (Schindler et al. 2010) or alcohol (Sperling et al. 2010) as Inhibitors,research,lifescience,medical well as stress-induced reinstatement of lever second pressing for cocaine (Beardsley et al. 2005), heroin (Zhou et al. 2013) or nicotine (Grella, Funk, Coen, Li, Lê, in revision) in rats. Taken together, these and our present data support the idea that KOR plays an important role in stress-induced drug seeking. However, one study reported that KOR blockade with JDTic did not affect footshock-induced reinstatement (Schank et al. 2012). The reasons for the discrepant findings are not clear. It is unlikely that nonspecific effects of nor-BNI produced the reduction in yohimbine-induced reinstatement we observed, as Schank et al. (2012) found that a dose of nor-BNI three times higher than what we used did not affect operant responding for sucrose.