Development of tolerance upon repeated administration with the GABA_B receptor positive allosteric modulator, COR659, on alcohol drinking in rodents

ABSTRACT

Background: Recent work has demonstrated that acute administration of the novel positive allosteric modulator of the GABA_B receptor, COR659, reduces several alcohol-related behaviors in rodents.

Objective: To assess whether COR659 continues to lessen alcohol intake after repeated administration, a fundamental feature of drugs with therapeutic potential.

Methods: Male C57BL/6J mice (n = 40) were exposed to daily 2-hour drinking sessions (20% (v/v) alcohol) under the 1-bottle “drinking in the dark” protocol and male Sardinian alcohol-preferring rats (n = 40) were exposed to daily 1-hour drinking sessions under the 2-bottle “alcohol (10%, v/v) vs water” choice regimen. COR659 (0, 10, 20, and 40 mg/kg in the mouse experiment; 0, 5, 10, and 20 mg/kg in the rat experiment) was administered intraperitoneally before 7 consecutive drinking sessions.

Results: Alcohol intake in vehicle-treated mice and rats averaged 2.5–3.0 and 1.5–1.6 g/kg/session, respectively, indicative of high basal levels. In both experiments, treatment with COR659 resulted in an initial, dose-related suppression of alcohol intake (up to 70–80% compared to vehicle treatment; P < .0005 and P < .0001 in mouse and rat experiments, respectively). The magnitude of the reducing effect of COR659 on alcohol drinking diminished progressively, until vanishing over the subsequent 2–4 drinking sessions.

Conclusion: COR659 effectively reduced alcohol intake in two different rodent models of excessive alcohol drinking. However, tolerance to the anti-alcohol effects of COR659 developed rapidly. If theoretically transposed to humans, these data would represent a possible limitation to the clinical use of COR659.

KEYWORDS:

• Positive allosteric modulator of the GABA_B receptor
• COR659
• alcohol drinking
• tolerance
• C57BL/6J mice
• Sardinian alcohol-preferring rats

Acknowledgements

The authors are grateful to Mrs. Carla Acciaro for breeding and care of sP rats.

Disclosure statement

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.”

Additional information

Funding

This work has been partially supported by grant no. [EA 17 14] from European Foundation for Alcohol Research (ERAB) and NIH Grants [AA028982, AA021667]. Authors from the University of Siena thank MIUR Progetto Dipartimenti di Eccellenza 2018-2022 for partial support.