Abstract
Rationale
Pre-clinical evidence implicates the GABAergic system in mediating the reinforcing effects of alcohol and offers a therapeutic target for alcohol use disorder (AUD). The orthosteric GABAB receptor agonist baclofen decreases alcohol self-administration in animals and alcohol use in humans; however side effects limit its utility. Pre-clinical evidence shows positive allosteric GABAB receptor modulators also decrease alcohol self-administration without untoward side effects.
Objectives
We assessed the impact of the novel GABAB-positive allosteric modulator ASP8062 and baclofen on operant alcohol self-administration and their potential non-specific effects.
Methods
The effects of ASP8062 (1 − 10 mg/kg, PO) and baclofen (0.3 − 3 mg/kg, IP) were evaluated in male and female rats lever pressing for alcohol (10%, w/v) under a fixed ratio 2 schedule of reinforcement. On the fourth consecutive day of vehicle, ASP8062 or baclofen administration, active and inactive lever presses, reinforcers earned, head entries, and estimated alcohol consumed were analyzed. Locomotor activity was assessed in separate groups of rats following dosing.
Results
Both ASP8062 and baclofen decreased alcohol self-administration and amount consumed (g/kg) in male and female rats. ASP8062 decreased operant alcohol self-administration to a greater extent in male rats, whereas baclofen was more efficacious in female rats. ASP8062 did not alter locomotor activity in either sex, whereas baclofen (3.0 mg/kg) decreased activity in male rats yet (1.0 mg/kg) increased activity in female rats.
Conclusions
ASP8062 decreases alcohol reinforcement like baclofen but without non-specific effects which are influenced by sex. Results support further development of ASP8062 as a potential treatment for AUD in humans.
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Acknowledgements
The authors would like to thank Miah D. Baker, Sergio A. Sanchez, and Saif Quadri for technical expertise in conducting the experiments at the University of Houston. We would also like to acknowledge Lauren N. Bradley and RTI International (Research Triangle Park, NC)/Pharmacotherapies for Alcohol and Substance Abuse (PASA) Consortium for administrative support. Additionally, we would also like to thank the Astellas Pharm Inc. (Ibaraki, Japan) ASP8062 team for comments on the manuscript and for providing ASP8062.
Funding
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Alcohol and Substance Abuse Research Program under Award No. W81XWH1820044 (sub-award: 3–312-0215031-52745L to CNH).
In conducting research using animals, the investigator adhered to the laws of the USA and regulations of the Department of Agriculture. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.
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Haile, C.N., Carper, B.A., Nolen, T.L. et al. The GABAB receptor positive allosteric modulator ASP8062 reduces operant alcohol self-administration in male and female Sprague Dawley rats. Psychopharmacology 238, 2587–2600 (2021). https://doi.org/10.1007/s00213-021-05881-0
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DOI: https://doi.org/10.1007/s00213-021-05881-0