Abnormalities in both the hippocampal region and in serotonergic transmission are evident in patients with schizophrenia. We previously found that rats with serotonergic lesions targeting the dorsal hippocampus show altered psychotropic drug-induced hyperlocomotion and prepulse inhibition (PPI), behavioural paradigms relevant to aspects of schizophrenia. The present study explored the effect of serotonin depletion (>70%) along the dorsoventral axis of the hippocampus, or of partial serotonin depletion (∼50%) in the ventral hippocampus, on PPI modulation by acute antipsychotic drug treatment. We also used receptor binding autoradiography to investigate the neurochemical basis of behavioural effects. Following micro-injection of 5,7-dihydroxytryptamine, neither hippocampal serotonin depletion or partial serotonin depletion in the ventral hippocampus altered baseline PPI, startle magnitude or startle habituation. Acute treatment with clozapine or haloperidol had minimal effects on PPI in these lesioned rats or sham-operated controls. In contrast, risperidone treatment increased PPI to a significantly greater extent in rats with hippocampal serotonin depletion, an effect which was most prominent at low prepulse intensities. Partial serotonin depletion in the ventral hippocampus did not alter PPI modulation by risperidone. Neither type of serotonergic lesion altered the densities of 5-HT(1A) or 5-HT(2A) receptors in the hippocampus; serotonin transporters or 5-HT(1A) autoreceptors on raphe cell bodies; or dopamine transporters, D(1) or D(2) receptors in forebrain regions efferent to the hippocampus and implicated in schizophrenia, such as the nucleus accumbens. However, levels of [(3)H]mesulergine binding to 5-HT(2C) receptors were increased by approximately 70% in the dorsal hippocampus of rats with serotonin depletion in this region, while those in the ventral hippocampus were unaffected. Therefore, despite intact baseline PPI, abnormal PPI regulation in rats with >70% serotonin depletion in the hippocampus was unmasked by acute risperidone treatment. Selective upregulation of 5-HT(2C) receptors in the dorsal, but not ventral, hippocampus of these lesioned rats suggests that hippocampal 5-HT(2C) receptors vary in their adaptability to changes in serotonergic tone along the dorsoventral axis. These findings suggest that 5-HT(2C) receptors in the dorsal hippocampus may contribute to risperidone-induced enhancement of PPI.