KK-92A, a novel GABAB receptor positive allosteric modulator, attenuates nicotine self-administration and cue-induced nicotine seeking in rats

Rationale: GABA_B receptors (GABA_BR) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABA_BR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABA_B receptor agonists such as baclofen.

Objectives: The present study was aimed at developing novel, selective, and potent GABA_BR PAMs with efficacy on abuse-related effects of nicotine.

Results: We synthetized ~100 analogs of BHF177, a GABA_BR PAM that has been shown to inhibit nicotine taking and seeking, and tested their activity in multiple cell-based functional assays. Among these compounds, KK-92A displayed superior PAM properties at the GABA_BR. Interestingly, our results revealed the existence of pathway-selective differential modulation of GABA_BR signaling by the structurally related GABA_BR allosteric modulators BHF177 and KK-92A. In vivo, similarly to BHF177, KK-92A inhibited intravenous nicotine self-administration under both fixed- and progressive-ratio schedules of reinforcement in rats. In contrast to BHF177, KK-92A had no effect on food self-administration. Furthermore, KK-92A decreased cue-induced nicotine-seeking behavior without affecting food seeking.

Conclusions: These results indicate that KK-92A is a selective GABA_BR PAM with efficacy in inhibition of the primary reinforcing and incentive motivational effects of nicotine, and attenuation of nicotine seeking, further confirming that GABA_BR PAMs may be useful antismoking medications.

Allosteric modulator; GABA receptor; GPCR; Nicotine; Relapse; Self-administration.