Blockade of ethanol reward by the kappa opioid receptor agonist U50,488H

Abstract

Alcoholism is a pervasive social problem, and thus understanding factors that regulate alcohol (ethanol) reward is important for designing effective therapies. One putative regulatory system includes the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin. Previously, we demonstrated that acute ethanol increased preprodynorphin expression via brain-derived neurotrophic factor (BDNF) in striatal neurons, and that blockade of the KOR attenuated decreases in ethanol intake observed following increased expression of BDNF. As high doses of KOR agonists can generate an aversive state, we hypothesized that endogenous dynorphin may regulate ethanol intake by interfering with the rewarding properties of ethanol. We found that low, nonaversive doses of the KOR agonist U50,488H blocked the rewarding properties of ethanol during conditioning, thus impairing the acquisition of conditioned place preference. Importantly, we demonstrate that U50,488H also inhibited the conditioned increase in locomotor activation normally observed in the ethanol-paired chamber on test day. Taken together, these data indicate that the KOR/dynorphin system may acutely regulate ethanol intake via inhibition of the rewarding properties of ethanol.

Figure 1. Activation of the kappa opioid receptor blocks acquisition of ethanol conditioned place preference

DBA mice were treated with first with saline or U50,488H (1 or 3 mg/kg, i.p.), followed 10 minutes later by treatment with saline or ethanol (2 mg/kg, i.p.) and immediate confinement in the drug-paired chamber on drug conditioning days, or similar treatments with saline only followed by confinement in the unpaired chamber on alternate days. Mice acquire a preference for the ethanol-paired chamber, an effect blocked by pretreatment with either dose of U50,488H during acquisition. Data are expressed as mean +/- S.E.M. CPP Score (difference between time spent in the drug-paired chamber during the 30-minute drug-free test as compared to the same chamber during the 30-minute drug-free pretest period). * p < 0.05, ** p < 0.005, *** p < 0.001 versus ethanol. n = 8 per treatment group.

Figure 2. Ethanol place conditioning increases locomotor activity in the ethanol-paired chamber, an effect which is blocked by U50,488H pretreatment during acquisition

DBA mice were treated with saline or U50,488H (1 or 3 mg/kg, i.p.), followed 10 minutes later by saline or ethanol (2 mg/kg, i.p.) on drug conditioning days. (A-F) Mean +/- S.E.M. locomotor activity during the pretest (white bars) and test (black bars) sessions for all treatment groups. (AC) Mice in the saline (A), 1 mg/kg U50,488H (B) and 3 mg/kg U50,488H (C) control groups show no change in locomotion following place conditioning training. n = 8 per treatment group. (D) Ethanol conditioning results in increased locomotor activity in the ethanol-paired chamber on test day, as compared to pretest day. ** p = 0.005 vs. pretest. n = 8 per treatment group. (E-F) Administration of 1 mg/kg (E) or 3 mg/kg (F) U50,488H prior to ethanol treatment blocks the conditioned increase in locomotor activity seen with ethanol alone. n = 8 per treatment group.