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

• Published in: Psychopharmacologia Vol. 222; no. 4; pp. 685 - 700
• Main Authors: Orrù, Alessandro, Fujani, Daniele, Cassina, Chiara, Conti, Mirko, Di Clemente, Angelo, Cervo, Luigi
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.08.2012; Springer
• Subjects: Addictive behaviors; Adult and adolescent clinical studies; Alcoholism; Alcoholism and acute alcohol poisoning; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Medical sciences; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Toxicology; Oral operant self-administration; C57BL/6J mice; Alcoholic beer; BHF177; Baclofen; Agonist; Muscle relaxant; Gabaergic agonist; Alcoholism; Rodentia; Oral administration; Self administration; Oral operant self-administration Alcoholic beer; Vertebrata; Mammalia; Allosteric regulation; Mouse; Antispasmodic agent; Animal; Gabaergic receptor B
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2672-6

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 GABA B agonist, and BHF177, a GABA B 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 self-administration 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 self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.