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Establishing an effective dose for chronic intracerebroventricular administration of clozapine in mice

Published online by Cambridge University Press:  19 August 2019

Dilhan Esen-Sehir
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany The Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt, Germany
Michael J. Courtney
Affiliation:
Neuronal Signalling Laboratory, Turku Centre for Biotechnology, University of Turku, Turku, Finland
Robert A. Bittner
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
Andreas Reif
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
Florian Freudenberg*
Affiliation:
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany
*
Author for correspondence: Florian Freudenberg, Email: Florian.Freudenberg@kgu.de

Abstract

Objective:

Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.

Methods:

Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.

Results:

None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.

Conclusion:

Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.

Type
Original Article
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

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