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

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Abstract

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 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.

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Acknowledgments

The authors are grateful to Dr. Klemens Kaupmann, Novartis Institutes for BioMedical Research, Basel, Switzerland for the generous gift of BHF117 and to J.D. Baggott for language editing.

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  1. Experimental Psychopharmacology, Department of Neuroscience, “Mario Negri” Institute for Pharmacological Research, Via La Masa 19, 20156, Milan, Italy

    Alessandro Orrù, Daniele Fujani, Chiara Cassina, Mirko Conti, Angelo Di Clemente & Luigi Cervo

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  1. Alessandro Orrù
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  2. Daniele Fujani
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  3. Chiara Cassina
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Correspondence to Alessandro Orrù.

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Orrù, A., Fujani, D., Cassina, C. et al. Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABAB receptors. Psychopharmacology 222, 685–700 (2012). https://doi.org/10.1007/s00213-012-2672-6

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