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Title: Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: Involvement of the GABAB and cannabinoid CB1 receptors
Authors: Maccioni, Paola
Colombo, Giancarlo
Lorrai, Irene
Zaru, Alessandro
Carai, Mauro A. M.
Gessa, Gian Luigi
Brizzi, Antonella 
Mugnaini, Claudia 
Corelli, Federico 
Keywords: GABAB receptor, positive allosteric modulator, Cannabinoid CB1 receptor, COR659, GS39783, AM4113, Alcohol Chocolate Oral self-administration Rat
Issue Date: 2017
Project: None 
Rationale and objectives COR659 [methyl2-(4-chlorophenylcarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate] is a new, positive allosteric modulator (PAM) of the GABAB receptor. This study evaluated whether COR659 shared with previously tested GABAB 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 GABAB 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 GABAB 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 GABAB 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.
ISSN: 1432-2072
DOI: 10.1007/s00213-017-4644-3
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