The Novel Positive Allosteric Modulator of the GABAB Receptor, KK-92A, Suppresses Alcohol Self-Administration and Cue-Induced Reinstatement of Alcohol Seeking in Rats.

Paola Maccioni,Patricia Mcdonald,Gian Luigi Gessa,Jessica Bratzu,Sang Yun,Giancarlo Colombo,Harshani Lawrence,Katarzyna Kaczanowska

doi:10.3389/fcell.2021.727576

Abstract

Positive allosteric modulators (PAMs) of the GABAB receptor (GABAB PAMs) are of interest in the addiction field due to their ability to suppress several behaviors motivated by drugs of abuse. KK-92A is a novel GABAB PAM found to attenuate intravenous self-administration of nicotine and reinstatement of nicotine seeking in rats. This present study was aimed at extending to alcohol the anti-addictive properties of KK-92A. To this end, Sardinian alcohol-preferring rats were trained to lever-respond for oral alcohol (15% v/v) or sucrose (0.7% w/v) under the fixed ratio (FR) 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, rats were exposed to tests with acutely administered KK-92A under FR5 and progressive ratio schedules of reinforcement and cue-induced reinstatement of previously extinguished alcohol seeking. KK-92A effect on spontaneous locomotor activity was also evaluated. Treatment with 10 and 20 mg/kg KK-92A suppressed lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol. Treatment with 20 mg/kg KK-92A reduced sucrose self-administration. Combination of per se ineffective doses of KK-92A (2.5 mg/kg) and the GABAB receptor agonist, baclofen (1 mg/kg), reduced alcohol self-administration. Treatment with 5, 10, and 20 mg/kg KK-92A suppressed reinstatement of alcohol seeking. Only treatment with 80 mg/kg KK-92A affected spontaneous locomotor activity. These results demonstrate the ability of KK-92A to inhibit alcohol-motivated behaviors in rodents and confirm that these effects are common to the entire class of GABAB PAMs. The remarkable efficacy of KK-92A is discussed in terms of its ago-allosteric properties.

Highlights

Positive allosteric modulation of the GABAB receptor has emerged as an important molecular mechanism to effectively control several alcohol-motivated behaviors
Acute treatment with KK92A suppressed, in a dose-related manner, lever-responding in the reinstatement session; post hoc test indicated that statistical significance was reached by treatment with all three doses [5 (P < 0.0005), 10 (P < 0.0001), and 20 (P < 0.0001) mg/kg KK-92A]
In Experiment 1A, the complete flatness of cumulative response pattern over the first 10 min of the session, observed after treatment with 20 mg/kg KK-92A, suggests that this dose of KK-92A abolished the typical “front-loading” of alcohol-drinking pattern of Sardinian alcoholpreferring (sP) rats exposed to alcohol self-administration sessions under the fixed ratio (FR) schedule of reinforcement

Summary

Introduction

Positive allosteric modulation of the GABAB receptor has emerged as an important molecular mechanism to effectively control several alcohol-motivated behaviors. The absence of persistent receptor activation (typical, on the other hand, of receptor agonists) results in a low propensity to induce receptor desensitization, explaining why repeated treatment with GABAB PAMs is associated with limited development of tolerance (see Urwyler, 2011, 2016). Together, these data indicate GABAB PAMs as active molecules having an improved therapeutic potential over baclofen

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Conclusion