Operant, oral alcoholic beer self-Administration by C57BL/6J mice: Effect of BHF177, a positive allosteric modulator of GABAB receptors

摘要

Rationale With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-Administration. Objectives The study aimed to develop an operant model of oral alcoholic beer self-Administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, on alcoholic beer self-Administration. Methods Mice were trained to self-Administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30- min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-Administration. Results Near-beer stably maintained operant oral selfadministration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-Administration increased (0.8-1.0 g/ kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-Administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-Administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-Also reduced near-beer self-Administration. Conclusions The operant model of oral alcoholic beer selfadministration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.