The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 microg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 microg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.