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PRECLINICAL STUDY: Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice

Authors


Christian A. Heidbreder, Department of Neuropsychopharmacology, Centre of Excellence for Drug Discovery in Psychiatry, GlaxoSmithKline, Via A. Fleming 4, 37135 Verona, Italy. E-mail: christian.a.heidbreder@gsk.com

ABSTRACT

The present study examined the effects of the acute intraperitoneal (i.p.) administration of the selective dopamine (DA) D3 receptor antagonist SB-277011A (10, 20 or 30 mg/kg i.p.) on the oral operant self-administration of alcohol in male C57BL/6N mice. These effects were compared with those of naltrexone (0.5, 1 and 2 mg/kg i.p.) and acamprosate (100, 200 and 400 mg/kg i.p.). Compared with vehicle, the acute administration of SB-277011A (10 or 20 mg/kg) did not significantly alter the operant self-administration of alcohol, whereas the 30 mg/kg dose significantly reduced alcohol intake (g/kg), the number of reinforcers, and the number of active lever presses. The oral self-administration of alcohol was not significantly altered by the acute administration of either naltrexone or acamprosate, compared with vehicle-treated mice. SB-277011A, naltrexone and acamprosate were also tested in a model of drug/cue-triggered reinstatement of alcohol-seeking behavior. In this model, neither naltrexone (2 mg/kg) nor acamprosate (400 mg/kg) prevented relapse to alcohol-seeking behavior. In contrast, SB-277011A significantly reduced reinstatement of alcohol seeking in a dose-dependent manner. Provided these results can be extrapolated to humans, they suggest that selective DA D3 receptor antagonists may be useful in the pharmacotherapeutic management of alcohol intake and prevention of relapse to alcohol-seeking behavior.

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