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

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.

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

“…KK-92A is one of the most recently synthesized GABAB PAMs (Li et al, 2017). In close agreement with the multiple and consistent existing literature data on GABAB PAMs (see above), its acute and repeated administration suppressed operant oral alcohol self-administration and cue-induced reinstatement of alcohol seeking in selectively bred Sardinian alcohol-preferring (sP) rats (Maccioni et al, 2021;Maccioni et al, 2022). The suppressing effects of KK-92A on alcohol self-administration occurred under both fixed ratio (FR; measure of the reinforcing properties of alcohol) and progressive ratio (PR; measure of the motivational properties of alcohol) schedules of reinforcement.…”

“…The suppressing effects of KK-92A on alcohol self-administration occurred under both fixed ratio (FR; measure of the reinforcing properties of alcohol) and progressive ratio (PR; measure of the motivational properties of alcohol) schedules of reinforcement. All these effects arose at doses of KK-92A remarkably lower than those inducing hypolocomotion and sedation (Maccioni et al, 2021); comparison of doses inducing the "desired" pharmacological effects (i.e., reduction of alcohol self-administration) and "unwanted" adverse effects (i.e., reduction of spontaneous locomotor activity) resulted in a therapeutic index higher than 8 (Maccioni et al, 2021). Finally, pretreatment with KK-92A synergistically potentiated the effect of baclofen on alcohol selfadministration in sP rats: combination of per se totally ineffective doses of both compounds produced indeed a marked reduction in lever-responding for alcohol (Maccioni et al, 2021).…”

“…All these effects arose at doses of KK-92A remarkably lower than those inducing hypolocomotion and sedation (Maccioni et al, 2021); comparison of doses inducing the "desired" pharmacological effects (i.e., reduction of alcohol self-administration) and "unwanted" adverse effects (i.e., reduction of spontaneous locomotor activity) resulted in a therapeutic index higher than 8 (Maccioni et al, 2021). Finally, pretreatment with KK-92A synergistically potentiated the effect of baclofen on alcohol selfadministration in sP rats: combination of per se totally ineffective doses of both compounds produced indeed a marked reduction in lever-responding for alcohol (Maccioni et al, 2021). Together, these data depict KK-92A as a promising agent for AUD treatment, thus rendering further scrutiny of its pharmacological profile a compelling research issue.…”

“…To address this research question, that bears evident translational relevance, KK-92A was administered intragastrically to sP rats exposed to the conventional FR schedule of reinforcement (Experiment 2), i.e. the same experimental procedure previously used to disclose the suppressing effect of intraperitoneally administered KK-92A on alcohol self-administration (Maccioni et al, 2021;Maccioni et al, 2022). Third, does the ability of KK-92A to suppress the motivational properties of alcohol under the PR schedule of reinforcement extend to an extinction responding (ER) procedure?…”

Editorial: Cell Biology, Physiology and Molecular Pharmacology of G Protein Coupled Receptors

“…Besides the acute signaling, GPCR, in direct or through crosstalk, also regulate the development of addictive diseases. In this area ( Maccioni et al, 2021 ), in their paper demonstrate that treatment with non-sedative doses of the novel positive-allosteric modulator (PAM) of the GABA-B receptor, KK-92A ([(4-(cycloheptylamino)-5-(4-(trifluoromethyl)phenyl)pyrimidin-2-yl)methanol]) potently and effectively suppressed operant oral alcohol self-administration and cue-induced reinstatement of alcohol-seeking in alcohol-preferring Sp rats. KK-92A has high potency and selectivity for GABA-B.…”