Kappa-opioid receptors and relapse-like drinking in long-term ethanol-experienced rats

Abstract.

Rationale: The role of the dynorphin/κ-opioid receptor system in ethanol reinforcement is unclear. Objective: Examination of the effects of the highly selective κ-opioid receptor agonist CI-977 (enadoline) and of the long-acting selective κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) on relapse-like drinking measured by the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats. Methods: Rats were either implanted with mini-osmotic pumps delivering 0 or 0.01 mg/kg per h CI-977 or received two injections (12 h apart) of nor-BNI (0 or 5 mg/kg i.p.) before re-presentation of alcohol after 2 weeks of alcohol deprivation in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received either acute CI-977 treatment (0, 0.003–0.1 mg/kg i.p.) or two injections (12 h apart) of nor-BNI (0 or 5 mg/kg i.p.) before a 23-h session. Results: Chronic CI-977 potentiated ethanol intake and preference during the ADE. Acute CI-977 dose-dependently reduced total lever pressing activity demonstrating an unspecific sedative effect, except for the lowest dose (0.003 mg/kg), which selectively increased lever pressing for ethanol during basal drinking. Nor-BNI did not affect relapse-like drinking at all. Conclusions: Stimulation of κ-opioid receptors can increase ethanol intake, at least in long-term ethanol-experienced rats. Since κ-opioid receptor agonists have aversive motivational consequences, increased ethanol drinking might be an attempt to counteract the aversive effects of this treatment. On the other hand, the nor-BNI experiments indicate that endogenous κ-opioid receptor stimulation does not seem to be involved in relapse-like drinking after protracted abstinence.