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Acute or subchronic clozapine treatment does not ameliorate prepulse inhibition (PPI) deficits in CPB-K mice with low levels of hippocampal NMDA receptor density

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Abstract

Introduction

The hypo-glutamatergic hypothesis of schizophrenia is based on clinical similarities between schizophrenia and phencyclidine (PCP)-induced psychosis in mentally healthy humans. Sensorimotor gating, as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), is impaired in schizophrenic patients. In animals, noncompetitive N-methyl-d-aspartate (NMDA) antagonists such as PCP disrupt PPI in a way that resembles the defect seen in schizophrenia. In a previous study with inbred mouse strains, low PPI levels have been demonstrated in CPB-K mice possessing low levels of hippocampal NMDA receptor densities. The present study was performed to test whether the low magnitude of PPI in CPB-K mice can be reversed by the atypical antipsychotic drug clozapine (CLZ).

Results

Before any treatment, CPB-K mice displayed a significant (p < 0.001) lower level in PPI and a significant (p < 0.001) higher ASR when compared to BALB/cJ mice known to have high hippocampal NMDA receptor densities. Acute and subchronic effects of a 2-week treatment with CLZ at daily doses of 5 and 10 mg/kg intraperitoneally, respectively, did not reveal any significant alteration of PPI levels in CPB-K mice. Nevertheless, the examination of motor behavior during nonstimulus trials provided a positive control for the drug’s effectiveness.

Conclusion

In summary, (1) this study confirmed our working hypothesis: Lower levels of hippocampal glutamatergic receptor densities correspond to lower sensorimotor gating in CPB-K mice, and (2) acute or subchronic treatment with CLZ did not elevate low PPI levels in CPB-K mice. Thus, further experiments will concentrate on other antipsychotic drugs to prove the predictive validity of this animal model.

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Abbreviations

AMPA:

α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid

ASR:

acoustic startle response to startle stimulus alone

CLZ:

clozapine

NMDA:

N-methyl-d-aspartate

NOSTIM:

nonstimulus

NMDA-R1:

NMDA receptor subunit R1

PCP:

phencyclidine

PPI:

prepulse inhibition of the startle reflex

PREPULSE:

prepulse only

PREPULSE + PULSE:

prepulse followed by the startle stimulus

PULSE-ALONE:

startle stimulus alone

5-HT:

serotonin

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Acknowledgments

This work was supported by the Federal Ministry of Education and Research of Germany (BMBF, FKZ 01ZZ0407).

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Authors and Affiliations

  1. Department of Psychiatry, Otto-von-Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany

    Rainer Wolf, Katrin Paelchen, Kay Matzke, Henrik Dobrowolny & Bernhard Bogerts

  2. Institute of Anatomy, Otto-von-Guericke University, Magdeburg, Germany

    Herbert Schwegler

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  1. Rainer Wolf
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  2. Katrin Paelchen
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  3. Kay Matzke
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  4. Henrik Dobrowolny
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Correspondence to Rainer Wolf.

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Wolf, R., Paelchen, K., Matzke, K. et al. Acute or subchronic clozapine treatment does not ameliorate prepulse inhibition (PPI) deficits in CPB-K mice with low levels of hippocampal NMDA receptor density. Psychopharmacology 194, 93–102 (2007). https://doi.org/10.1007/s00213-007-0824-x

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  • DOI: https://doi.org/10.1007/s00213-007-0824-x

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