Positive Allosteric Modulation of GABA subB/sub Receptors Ameliorates Sensorimotor Gating in Rodent Models

摘要

Summary Background Converging evidence points to the involvement of γ ‐amino‐butyric acid B receptors ( GABA B R s) in the regulation of information processing. We previously showed that GABA B 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 GABA B 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 S prague‐ D awley rats and C 57 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 GABA B 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 GABA B R s in the modulation of sensorimotor gating and point to their PAM s as a novel promising tool for antipsychotic treatment, with fewer side effects than GABA B R agonists.