Up to now, it is not yet clear whether and how clozapine and its metabolites are metabolized in neuronal cells. The interconversion of clozapine and its metabolites, clozapine-N-oxide and norclozapine, was studied in the hippocampal neuronal in vitro system of HT22 cells. Clinically relevant concentrations of clozapine (200+400 ng/ml) and its metabolites (100+200 ng/ml) were used for the examination of the metabolizing effects after short- (4 h) and long- (24 h) term incubation. Two-way analysis of variance revealed a significant decrease of clozapine (P<0.01) and norclozapine (P<0.01) levels in the supernatants of HT22 cells after the treatment procedures. Student-Newman-Keuls tests showed a significant decrease of clozapine 400 after 24 h of incubation (P=0.01) as well as of all concentrations of norclozapine. No significant treatment effects were found for the clozapine-N-oxide degradation. Using semi-quantification by reverse transcriptase-polymerase chain reaction methods, we could show a significant increase of cytochrome P450 (CYP) 1A2 mRNA levels (P<0.05) after clozapine treatment with 200 ng/ml. The results of the present study strongly suggest that clozapine and norclozapine are metabolized in hippocampal neuronal HT22 cells by CYP1A2, whereas the levels of clozapine-N-oxide were not affected. Moreover, CYP1A2 mRNA levels were significantly changed by incubation with clozapine 200.