Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: involvement of the GABAB and cannabinoid CB1 receptors

Abstract

Rationale and objectives: COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABA_B receptor. This study evaluated whether COR659 shared with previously tested GABA_B PAMs the capacity to reduce alcohol self-administration in rats.

Results: Treatment with non-sedative doses of COR659 (2.5, 5, and 10 mg/kg; i.p.) suppressed lever-responding for alcohol (15% v/v) in Sardinian alcohol-preferring (sP) rats under the fixed ratio (FR) 4 (FR4) and progressive ratio (PR) schedules of reinforcement; COR659 was more potent and effective than the reference GABA_B PAM, GS39783. Treatment with COR659, but not GS39783, suppressed (a) lever-responding for a sucrose solution (1-3% w/v) in sP rats under the FR4 and PR schedules, (b) lever-responding for a chocolate solution [5% (w/v) Nesquik®] in Wistar rats under the FR10 and PR schedules, and (c) cue-induced reinstatement of chocolate seeking in Wistar rats. Treatment with COR659 was completely ineffective on lever-responding (FR10) for regular food pellets in food-deprived Wistar rats. Pretreatment with the GABA_B receptor antagonist, SCH50911, partially blocked COR659-induced reduction of alcohol self-administration, being ineffective on reduction of chocolate self-administration. Pretreatment with the cannabinoid CB₁ receptor antagonist, AM4113, fully blocked COR659-induced reduction of chocolate self-administration, being ineffective on reduction of alcohol self-administration.

Conclusions: COR659 might exert its behavioral effects via a composite mechanism: (i) positive allosteric modulation of the GABA_B receptor, responsible for a large proportion of reduction of alcohol self-administration; (ii) an action at other receptor system(s), including the cannabinoid CB₁ receptor, through which COR659 affects seeking and consumption of highly palatable foods.

Keywords: AM4113; Alcohol; COR659; Cannabinoid CB1 receptor; Chocolate; GABAB receptor; GS39783; Oral self-administration; Positive allosteric modulator; Rat.