Effects of clozapine on behavioral and metabolic traits relevant for schizophrenia in two mouse strains

Abstract

Rationale: Schizophrenia is a heterogeneous syndrome both at the etiological and clinical levels. In particular, patients with schizophrenia exhibit important variability in their therapeutic and metabolic responses to clozapine, an antipsychotic medication.

Objective: Here, we determine whether two mouse strains show differing clozapine responses with respect to weight gain, enhancement of prepulse inhibition of acoustic startle, and reversal of amphetamine-induced locomotion. Observed between-strain differences may be partly due to genetic factors that can be subsequently mapped using quantitative genetic approaches.

Methods: We treated the A/J and C57BL/6J inbred mouse strains with clozapine for 22 days. Prepulse inhibition and amphetamine-induced locomotion were measured after 3-4 days of clozapine treatment and again after 21-22 days of treatment. Weight gain was also monitored during treatment. RESULTS. Three-day treatment with clozapine increased prepulse inhibition in both strains. Four-day clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain. Long-term (21-22 days) clozapine treatment did not affect these behaviors in either strain. After an initial weight loss during the first 5 days, clozapine (4 mg/kg) induced a significant weight gain in both strains.

Conclusions: The reversal of schizophrenia-related behaviors after short-term, but not long-term, clozapine treatment is consistent with other rodent studies. Although short-term clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain, strain differences in amphetamine responses confound the interpretation of these results; therefore, quantitative genetic approaches may be difficult to carry out with this trait. In contrast, enhancement of prepulse inhibition after three days of clozapine treatment and weight gain induced by clozapine are relatively straightforward to quantify, making these trait more amenable to quantitative genetic approaches.