Reducing effect of the novel positive allosteric modulator of the GABAB receptor, COR659, on binge-like alcohol drinking in male mice and rats

Abstract

Rationale: Binge drinking (BD) is a widespread drinkingpattern that may contribute to promote the development of alcohol use disorder (AUD). The comprehension of its neurobiological basis and the identification of molecules that may prevent BD are critical. Preclinical studies demonstrated that positive allosteric modulators (PAMs) of the GABA_B receptor effectively reduced, and occasionally suppressed, the reinforcing and motivational properties of alcohol in rodents, suggesting their potential use as pharmacotherapy for AUD, including BD. Recently, we demonstrated that COR659, a novel GABA_B PAM, effectively reduced (i) alcohol drinking under the 2-bottle choice regimen, (ii) alcohol self-administration under both fixed and progressive ratio schedules of reinforcement, and (iii) cue-induced reinstatement of alcohol-seeking behavior in Sardinian alcohol-preferring (sP) rats.

Objectives: The present study investigated whether the "anti-alcohol" properties of COR659 extend to binge-like drinking in rodents.

Methods: COR659 was tested on the "drinking in the dark" (DID) paradigm in C57BL/6J mice and the 4-bottle "alcohol [10%, 20%, 30% (v/v)] versus water" choice regimen with limited and unpredictable access to alcohol in sP rats.

Results: Acute administration of non-sedative doses of COR659 (10, 20, and 40 mg/kg; i.p.) effectively and selectively suppressed the intake of intoxicating amounts of alcohol (> 2 g/kg) consumed by C57BL/6J mice and sP rats exposed to these binge-like drinking experimental procedures.

Conclusions: The present data demonstrate the ability of COR659 to suppress binge-like drinking in rodents and strengthen the hypothesis that GABA_B PAMs may represent a potentially effective pharmacotherapy for alcohol misuse.

Keywords: 4-bottle “alcohol versus water” choice regimen; Binge drinking; C57BL/6J mice; COR659; Positive allosteric modulators of the GABAB receptor; Sardinian alcohol-preferring rats; “Drinking in the dark”.