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 (GABABRs) in the regulation of information processing. We previously showed that GABABR 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 GABABR-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 C57BL/6 mice. Furthermore, we verified whether rac-BHFF ameliorated the spontaneous PPI impairments in DBA/2J mice.


RESULTS
rac-BHFF dose-dependently countered the PPI deficits across all three models, in a fashion akin to the GABABR 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 GABABRs in the modulation of sensorimotor gating and point to their PAMs as a novel promising tool for antipsychotic treatment, with fewer side effects than GABABR agonists.
"Guy Everett" Laboratory, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy; Tourette Syndrome Center, University of Cagliari, Cagliari, Italy.
Roberto
R
Frau
Valentina
V
Bini
Giuliano
G
Pillolla
Pari
P
Malherbe
Alessandra
A
Pardu
Andrew W
AW
Thomas
Paola
P
Devoto
Marco
M
Bortolato
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D023421:Models, Animal; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology*; D055139:Sensory Gating / Q000187:drug effects / Q000502:physiology*
C532129:(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; D001572:Benzofurans; D018080:Receptors, GABA-B
DBA/2J mice; GABAB receptors; NMDA receptors; Prepulse inhibition of the startle; Schizophrenia; Sensorimotor gating