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

• Published in: Alcohol (Fayetteville, N.Y.) N.Y.), 2023-11, Vol.112, p.61-70
• Main Authors: Maccioni, Paola, Kaczanowska, Katarzyna, Lobina, Carla, Regonini Somenzi, Laura, Bassareo, Valentina, Gessa, Gian Luigi, Lawrence, Harshani R., McDonald, Patricia, Colombo, Giancarlo
• Format: Article
• Language: English
• Subjects: 2-bottle choice alcohol drinking; alcohol taste and palatability; extinction responding for alcohol; KK-92A; operant alcohol self-administration positive allosteric modulation of the GABAB receptor
• ISSN: 0741-8329; 1873-6823
• DOI: 10.1016/j.alcohol.2023.07.004

Recent studies have demonstrated the ability of the positive allosteric modulator (PAM) of the GABAB receptor (GABAB 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 GABAB PAMs may represent a novel class of ligands with therapeutic potential for treating alcohol use disorder. •KK-92A is a novel positive allosteric modulator of the GABAB receptor.•Treatment with KK-92A reduced alcohol drinking in alcohol-preferring sP rats.•KK-92A reduced alcohol self-administration in sP rats when given intragastrically.•Treatment with KK92A reduced alcohol-seeking behavior in sP rats.•KK92A did not alter alcohol palatability in sP rats.