Delving into the reducing effects of the GABAB positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats

Paola Maccioni; Katarzyna Kaczanowska; Carla Lobina; Laura Regonini Somenzi; Valentina Bassareo; Gian Luigi Gessa; Harshani R Lawrence; Patricia McDonald; Giancarlo Colombo

doi:10.1016/j.alcohol.2023.07.004

Delving into the reducing effects of the GABA_B positive allosteric modulator, KK-92A, on alcohol-related behaviors in rats

Alcohol. 2023 Nov:112:61-70. doi: 10.1016/j.alcohol.2023.07.004. Epub 2023 Jul 24.

Authors

Paola Maccioni¹, Katarzyna Kaczanowska², Carla Lobina¹, Laura Regonini Somenzi¹, Valentina Bassareo³, Gian Luigi Gessa¹, Harshani R Lawrence⁴, Patricia McDonald⁵, Giancarlo Colombo⁶

Affiliations

¹ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato (CA), Italy.
² Department of Chemistry, Scripps Research, La Jolla, California, United States.
³ Department of Biomedical Sciences, University of Cagliari, Monserrato (CA), Italy.
⁴ Chemical Biology Core, Moffitt Cancer Center, Tampa, Florida, United States.
⁵ Department of Cancer Physiology, Moffitt Cancer Center, Tampa, Florida, United States.
⁶ Neuroscience Institute, Section of Cagliari, National Research Council of Italy, Monserrato (CA), Italy. Electronic address: giancarlo.colombo@cnr.it.

PMID: 37495087
DOI: 10.1016/j.alcohol.2023.07.004

Abstract

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABA_B receptor (GABA_B PAM), KK-92A, to suppress operant alcohol self-administration and reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to scrutinize the suppressing effects of KK-92A on alcohol-related behaviors; to this end, four separate experiments were conducted to address just as many new research questions, some of which bear translational value. Experiment 1 found that 7-day treatment with KK-92A (0, 5, 10, and 20 mg/kg, intraperitoneally [i.p.]) effectively reduced alcohol intake in male sP rats exposed to the home-cage 2-bottle "alcohol (10% v/v) vs. water" choice regimen with 1 hour/day limited access, extending to excessive alcohol drinking the ability of KK-92A to suppress operant alcohol self-administration. Experiment 2 demonstrated that the ability of KK-92A to reduce lever-responding for alcohol was maintained also after acute, intragastric treatment (0, 20, and 40 mg/kg) in female sP rats trained to lever-respond for 15% (v/v) alcohol under the fixed ratio 5 schedule of reinforcement. In Experiment 3, acutely administered KK-92A (0, 5, 10, and 20 mg/kg, i.p.) dampened alcohol-seeking behavior in female sP rats exposed to a single session under the extinction responding schedule. Experiment 4 used a taste reactivity test to demonstrate that acute treatment with KK-92A (0 and 20 mg/kg, i.p.) did not alter either hedonic or aversive reactions to a 15% (v/v) alcohol solution in male sP rats, ruling out that KK-92A-induced reduction of alcohol drinking and self-administration could be due to alterations in alcohol palatability. Together, these results enhance the behavioral pharmacological profile of KK-92A and further strengthen the notion that GABA_B PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder.

Keywords: 2-bottle choice alcohol drinking; KK-92A; alcohol taste and palatability; extinction responding for alcohol; operant alcohol self-administration positive allosteric modulation of the GABA(B) receptor.