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

Rationale. Because of its high palatability, near-beer has been successfully used in rats as vehicle to induce large amount of ethanol oral self-administration. Objectives. To develop an operant model of oral alcoholic-beer self-administration promoting in free-feeding C57BL/6J mice a stable intake of pharmacologically relevant amount of ethanol. To assess the model predictive validity evaluating the ability of baclofen, a GABAB agonist, and BHF177, a GABAB positive allosteric modulator, to influence alcoholic-beer self-administration. Methods. Mice were trained to self-administer, under a fixed-ratio 3 schedule of reinforcement, 10 µL of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30-min sessions. The effects of alcoholic-beer self-administration on motor coordination (rotarod), locomotor activity (open field and automated cages) and anxiety-like behaviour (elevated plus maze) were evaluated. Moreover, the ability of baclofen (1.25-5 mg/kg, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) to modulate 9% alcoholic-beer and near-beer self-administration was assessed. Results. Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer, decreased the number of active lever presses whereas the corresponding amount of ethanol self-administered remained stable (0.8-1.0 g/kg/30-min). Motor impairment and a slight, but consistent, hyper-locomotion was observed when the amount of ethanol self-administered with beer was higher than 1.3 g/kg/30-min and 0.9-1.0 g/kg/30-min, respectively. Finally, BHF177 (15 mg/kg) preferentially reduced 9% alcoholic-beer self-administration whereas higher dose (30 mg/kg), similarly to baclofen (5 mg/kg), reduced also near-beer self-administration. Conclusions. The operant model of oral alcoholic-beer self-administration in C57BL/6J mice should prove a useful tool to study ethanol reinforced behaviours and to identify potential candidate compounds in the pharmacological management of alcohol addiction