Repeated antipsychotic treatment may produce adaptive changes ranging from cytoarchitectural rearrangements to synaptic modifications that might contribute to clinical improvement. We performed a prolonged treatment (2 wk) with the first-generation antipsychotic (FGA) haloperidol (1 mg/kg) and the second-generation antipsychotic (SGA) olanzapine (2 mg/kg twice daily) and analysed the expression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in rat hippocampus and prefrontal cortex via immunohistochemistry. We found a regional- and drug-selective increase of PSA-NCAM expression in prefrontal cortex of olanzapine-treated rats with no effects in hippocampus; conversely, haloperidol did not produce a change in either brain region. Our findings reveal a possible role for PSA-NCAM in the mechanism of action of the SGA olanzapine adding complexity as well as specificity to the molecular changes set in motion by this drug.