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 red label violin strings color code 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 cucharas reservoir 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.