Competitive NMDA receptor antagonists disrupt prepulse inhibition without reduction of startle amplitude in a dopamine receptor-independent manner in mice

Abstract Prepulse inhibition is thought to reflect the operation of the sensorimotor gating system in the brain, and is reduced in schizophrenic patients and in animals treated with non-competitive NMDA receptor antagonists such as phencyclidine and (+)-5-methyl-10,11-dihydro-5 H -dibenzo[ a , d ]cyclohepten-5,10-imine ((+)-MK-801). Previously, we reported that a competitive NMDA receptor antagonist, cis -4-phosphonomethyl-2-piperidine-carboxylate hydrochloride (CGS 19755), also disrupts prepulse inhibition concomitantly with a marked reduction of startle amplitude elicited by pulse alone in rats. In the present study, the effect of NMDA receptor antagonists on prepulse inhibition was tested in mice. In addition, involvement of the dopaminergic system in CGS 19755-induced disruption of prepulse inhibition was examined. When CGS 19755 was subcutaneously administered at 40 and 80 mg/kg, prepulse inhibition was disrupted without any change in the startle amplitude elicited by pulse alone. Intracerebroventricularly administered CGS 19755 disrupted prepulse inhibition at dosages of 0.1 and 0.2 μg/mouse. The same dosages of R -3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ( R -CPP), another competitive NMDA receptor antagonist, also decreased prepulse inhibition, while its less active enantiomer, S -CPP, did not affect prepulse inhibition at 0.2 μg/mouse (i.c.v.). A typical neuroleptic, haloperidol, did not significantly improve CGS 19755 (40 mg/kg s.c.)-induced disruption of prepulse inhibition. These results suggest that the disruption of prepulse inhibition by CGS 19755 and R -CPP is NMDA receptor-mediated and dopamine receptor-independent.