Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration

Exposure to inescapable stressors increases both the rewarding properties and self-administration of cocaine through the signaling of the kappa-opioid receptor (KOR), but the effect of this signaling on other reinforcing agents remains unclear. The objective of this study is to test the hypothesis that signaling of the KOR mediates the forced swim stress (FSS)-induced potentiation of ethanol reward and self-administration. Male C57Bl/6J mice were tested in a biased ethanol-conditioned place preference (CPP) procedure, and both C57Bl/6J and prodynorphin gene-disrupted (Dyn -/-) mice were used in two-bottle free choice (TBC) assays, with or without exposure to FSS. To determine the role of the KOR in the resulting behaviors, the KOR agonist U50,488 (10 mg/kg) and antagonist nor-binaltorphimine (nor-BNI, 10 mg/kg) were administered prior to parallel testing. C57Bl/6J mice exposed to repeated FSS 5 min prior to daily place conditioning with ethanol (0.8 g/kg) demonstrated a 4.4-fold potentiation of ethanol-CPP compared to unstressed mice that was prevented by nor-BNI pretreatment. Likewise, pretreatment with U50,488 90 min prior to daily ethanol place conditioning resulted in a 2.8-fold potentiation of ethanol-CPP. In the TBC assay, exposure to FSS significantly increased the consumption of 10% (v/v) ethanol by 19.3% in a nor-BNI-sensitive manner. Notably, Dyn -/- mice consumed a similar volume of ethanol as wild-type littermates and C57Bl/6J mice, but did not demonstrate significant stress-induced increases in consumption. These data demonstrated a stress-induced potentiation of the rewarding effects and self-administration of ethanol mediated by KOR signaling.