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

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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.

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Acknowledgements

This work was funded by grants awarded to P.B. and R.J. from RGS Genome, Inc., the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the Canadian Institutes of Health Research (CIHR). We thank Jesse Carlevaris, Yves Gingras, and Ying Zhang for their expert and careful assistance.

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Authors and Affiliations

  1. Department of Neurology and Neurosurgery, McGill University and Douglas Hospital Research Centre, Montréal, Québec, H4H 1R3, Canada

    Jean Mary Zarate, Patricia Boksa & Ridha Joober

  2. Department of Psychiatry, McGill University and Douglas Hospital Research Centre, Montréal, Québec, H4H 1R3, Canada

    Patricia Boksa, Trino Baptista & Ridha Joober

  3. Douglas Hospital Research Centre, 6875 LaSalle Boulevard, Verdun, Québec, H4H 1R3, Canada

    Ridha Joober

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  1. Jean Mary Zarate
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  2. Patricia Boksa
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  3. Trino Baptista
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  4. Ridha Joober
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Correspondence to Ridha Joober.

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Zarate, J.M., Boksa, P., Baptista, T. et al. Effects of clozapine on behavioral and metabolic traits relevant for schizophrenia in two mouse strains. Psychopharmacology 171, 162–172 (2004). https://doi.org/10.1007/s00213-003-1553-4

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  • DOI: https://doi.org/10.1007/s00213-003-1553-4

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