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

Prepulse inhibition is thought to reflect the operation of the sensorimotor gating system in the brain, and is reduced in schizophrenic patients and i n animals treated with non-competitive NMDA receptor antagonists such as ph encyclidine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine ((+)-MK-801). Previously, we reported that a competitive NMDA recepto r 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 pres ent study, the effect of NMDA receptor antagonists on prepulse inhibition w as tested in mice. In addition, involvement of the dopaminergic system in C GS 19755-induced disruption of prepulse inhibition was examined. When CGS 1 9755 was subcutaneously administered at 40 and 80 mg/kg, prepulse inhibitio n was disrupted without any change in the startle amplitude elicited by pul se alone. Intracerebroventricularly administered CGS 19755 disrupted prepul se inhibition at dosages of 0.1 and 0.2 mu g/mouse. The same dosages of R-3 -(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), another compet itive NMDA receptor antagonist, also decreased prepulse inhibition, while i ts less active enantiomer, S-CPP, did not affect prepulse inhibition at 0.2 mu g/mouse (i.c.v.). A typical neuroleptic, haloperidol, did not significa ntly improve CGS 19755 (40 mg/kg s.c.)-induced disruption of prepulse inhib ition. These results suggest that the disruption of prepulse inhibition by CGS 19755 and R-CPP is NMDA receptor-mediated and dopamine receptor-indepen dent. (C) 1999 Elsevier Science B.V. All rights reserved.