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Psychopharmacology (Berl). 2007 Sep;194(1):93-102. Epub 2007 May 31.

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



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).


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.


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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