Prepulse inhibition (PPI) of the startle response is used as a measure of sensorimotor inhibitory processes. Deficits in PPI have been found in patients with schizophrenia, obsessive compulsive disorder (OCD) and Huntington's disease. PPI can also be disrupted in animals through manipulations that augment serotonergic activity, such as administration of the serotonin (5-HT) agonists 8-OH-DPAT, RU 24969 and DOI. In the present experiment the identity of the 5-HT receptor subtype that mediates the DOI-induced disruption of PPI was examined. Dose-response studies revealed that the novel 5-HT(2A) antagonist, MDL 100,907 (0.01, 0.1 and 1.0mg/kg, s.c.), but not the new 5-HT(2C) antagonist SDZ SER 082 (0.125, 0.25 and 0.5mg/kg, s.c.), prevented the loss of PPI induced by DOI (0.25 or 0.5mg/kg, s.c.). The results support the hypothesis that the 5-HT(2A) receptor is involved in the modulation of sensorimotor gating. Because deficits in PPI are used as a model of sensorimotor gating abnormalities found in schizophrenia, the present study supports the view that MDL 100,907 may be a novel atypical antipsychotic. Studies of the serotonergic substrates of PPI may provide a model of the possible serotonergic role in the sensorimotor gating abnormalities in schizophrenia and OCD patients.