Paola Maccioni1, Giancarlo Colombo2, Irene Lorrai1, Alessandro Zaru1,3, Mauro A M Carai4, Gian Luigi Gessa1,3, Antonella Brizzi5, Claudia Mugnaini5, Federico Corelli5. 1. Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042, Monserrato (CA), Italy. 2. Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042, Monserrato (CA), Italy. colomb@unica.it. 3. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042, Monserrato (CA), Italy. 4. Cagliari Pharmacological Research, 09127, Cagliari (CA), Italy. 5. Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100, Siena (SI), Italy.
Abstract
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.
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.
Authors: Paola Maccioni; Andrew W Thomas; Mauro A M Carai; Gian Luigi Gessa; Pari Malherbe; Giancarlo Colombo Journal: Drug Alcohol Depend Date: 2010-01-20 Impact factor: 4.492
Authors: Paola Maccioni; Mauro A M Carai; Klemens Kaupmann; Sébastien Guery; Wolfgang Froestl; Kimberly A Leite-Morris; Gian Luigi Gessa; Giancarlo Colombo Journal: Alcohol Clin Exp Res Date: 2009-07-01 Impact factor: 3.455
Authors: Elizabeth M Burnette; Steven J Nieto; Erica N Grodin; Lindsay R Meredith; Brian Hurley; Karen Miotto; Artha J Gillis; Lara A Ray Journal: Drugs Date: 2022-02-08 Impact factor: 9.546