Positive Allosteric Modulation of GABAB Receptors Ameliorates Sensorimotor Gating in Rodent Models.

Background Converging evidence points to the involvement of γ-amino-butyric acid B receptors ( GABAB Rs) in the regulation of information processing. We previously showed that GABAB R agonists exhibit antipsychotic-like properties in rodent models of sensorimotor gating deficits, as measured by the prepulse inhibition ( PPI) of the acoustic startle reflex. The therapeutic potential of these agents, however, is limited by their neuromuscular side effects; thus, in this study, we analyzed whether rac- BHFF, a potent GABAB R-positive allosteric modulator ( PAM), could counter spontaneous and pharmacologically induced PPI deficits across various rodent models. Methods We tested the antipsychotic effects of rac- BHFF on the PPI deficits caused by the N-methyl- D-aspartate glutamate receptor antagonist dizocilpine, in Sprague- Dawley rats and C57 BL/6 mice. Furthermore, we verified whether rac- BHFF ameliorated the spontaneous PPI impairments in DBA/2 J mice. Results rac- BHFF dose-dependently countered the PPI deficits across all three models, in a fashion akin to the GABAB R agonist baclofen and the atypical antipsychotic clozapine; in contrast with these compounds, however, rac- BHFF did not affect startle magnitude. Conclusions The present data further support the implication of GABAB Rs in the modulation of sensorimotor gating and point to their PAMs as a novel promising tool for antipsychotic treatment, with fewer side effects than GABAB R agonists. [ABSTRACT FROM AUTHOR]