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

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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.

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Acknowledgements

The authors are grateful to Mrs. Carla Acciaro for animal breeding and care and Ms. Anne Farmer for language editing of the manuscript. This work has been partially supported by grants (a) no. CRP-17596 from Regione Autonoma della Sardegna (L.R. 7 agosto 2007, n. 7) and (b) EA 13 20 from European Foundation for Alcohol Research (ERAB).

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Authors and Affiliations

  1. Neuroscience Institute, Section of Cagliari, National Research Council of Italy, 09042, Monserrato (CA), Italy

    Paola Maccioni, Giancarlo Colombo, Irene Lorrai, Alessandro Zaru & Gian Luigi Gessa

  2. Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042, Monserrato (CA), Italy

    Alessandro Zaru & Gian Luigi Gessa

  3. Cagliari Pharmacological Research, 09127, Cagliari (CA), Italy

    Mauro A. M. Carai

  4. Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100, Siena (SI), Italy

    Antonella Brizzi, Claudia Mugnaini & Federico Corelli

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  1. Paola Maccioni
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  2. Giancarlo Colombo
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  3. Irene Lorrai
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  4. Alessandro Zaru
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  5. Mauro A. M. Carai
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  9. Federico Corelli
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Correspondence to Giancarlo Colombo.

Ethics declarations

The experimental procedures employed in the present study were (a) in accordance with European Directive no. 2010/63/EU and subsequent Italian Legislative Decree no. 26, March 4, 2014, on the “Protection of animals used for scientific purposes” and (b) approved by the Italian Ministry of Health (authorization no. 342/2016-PR).

Conflict of interest

Mauro A.M. Carai, Giancarlo Colombo, Federico Corelli, Gian Luigi Gessa, Claudia Mugnaini, and Paola Maccioni are inventors on patent application no. 102016000030477 entitled “Use of 2-(acylamino)thiophene derivatives for the treatment of food dependence.”

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Maccioni, P., Colombo, G., Lorrai, I. et al. Suppressing effect of COR659 on alcohol, sucrose, and chocolate self-administration in rats: involvement of the GABAB and cannabinoid CB1 receptors. Psychopharmacology 234, 2525–2543 (2017). https://doi.org/10.1007/s00213-017-4644-3

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