Activation of GABA(B) receptors reverses spontaneous gating deficits in juvenile DBA/2J mice.
BACKGROUND
Gamma-amino-butyric acid (GABA)(B) receptors play a key role in the pathophysiology of psychotic disorders. We previously reported that baclofen, the prototypical GABA(B) agonist, elicits antipsychotic-like effects in the rat paradigm of prepulse inhibition (PPI) of the startle, a highly validated animal model of schizophrenia.


OBJECTIVE
We studied the role of GABA(B) receptors in the spontaneous PPI deficits displayed by DBA/2J mice.


METHODS
We tested the effects of baclofen (1.25-5 mg/kg, intraperitoneal [i.p.]) in DBA/2J and C57BL/6J mice, in comparison to the antipsychotic drugs haloperidol (1 mg/kg, i.p.) and clozapine (5 mg/kg, i.p.). Furthermore, we investigated the expression of GABA(B) receptors in the brain of DBA/2J and C57BL/6J mice by quantitative autoradiography.


RESULTS
Baclofen dose-dependently restored PPI deficit in DBA/2J mice, in a fashion similar to the antipsychotic clozapine (5 mg/kg, i.p.). This effect was reversed by pretreatment with the GABA(B) antagonist SCH50211 (50 mg/kg, i.p.). In contrast, baclofen did not affect PPI in C57BL/6J mice. Finally, quantitative autoradiographic analyses assessed a lower GABA(B) receptor expression in DBA/2J mice in comparison to C57BL/6J controls in the prefrontal cortex and hippocampus but not in other brain regions.


CONCLUSIONS
Our data highlight GABA(B) receptors as an important substrate for sensorimotor gating control in DBA/2J mice and encourage further investigations on the role of GABA(B) receptors in sensorimotor gating, as well as in the pathophysiology of psychotic disturbances.
Bortolato
Marco
M
Department of Neuroscience "Bernard B. Brodie", University of Cagliari, Cittadella Universitaria, S.S.554 Km 4,500, 09042, Monserrato (CA), Italy. marco.bortolato@inwind.it
Frau
Roberto
R
Orrù
Marco
M
Piras
A Paola
AP
Fà
Mauro
M
Tuveri
Antonella
A
Puligheddu
Monica
M
Gessa
Gian Luigi
GL
Castelli
M Paola
MP
Mereu
Giampaolo
G
Marrosu
Francesco
F
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001345:Autoradiography; D001418:Baclofen / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D003024:Clozapine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology*
D014150:Antipsychotic Agents; D018755:GABA Agonists; D018080:Receptors, GABA-B; D001418:Baclofen; D003024:Clozapine; D006220:Haloperidol