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Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo

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Abstract

Rationale

The basis of the unique clinical profile of the antipsychotic clozapine is not yet elucidated. Brain histamine receptors may play a role in schizophrenia and its treatment, but their involvement in the profile of clozapine remained unknown.

Objectives

We explored the properties of clozapine and its two metabolites, N-desmethylclozapine (NDMC) and clozapine N-oxide, at the four human histaminergic receptors. We compared their active concentrations with their blood concentrations in patients treated by clozapine. We investigated the changes in receptor densities induced in rat brain by repeated administration of a therapeutic dose of clozapine.

Results

Clozapine and NDMC behaved as very potent, and partial, H1-receptor inverse agonists, weak, and full, H2-receptor inverse agonists, moderate, and protean, H3-receptor agonists, and moderate, and partial, H4-receptor agonists. Taking into account their micromolar mean blood concentrations found in 75 treated patients, and assuming that they are enriched in human brain as they are in rat brain, a full occupation of H1-, H3-, and H4-receptors, and a partial occupation of H2 receptors, is expected. In agreement, repeated administration of clozapine at a therapeutic dose (20 mg/kg/day for 20 days) induced an up-regulation of H1- and H2-receptors in rat brain.

Conclusions

Clozapine and its active metabolite NDMC interact with the four human histamine receptors at clinically relevant concentrations. This interaction may substantiate, at least in part, the atypical antipsychotic profile of clozapine, as well as its central and peripheral side effects such as sedation and weight gain.

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Acknowledgements

This study was supported by INSERM. M. Humbert-Claude and F. Gbahou were supported by a grant from the Fondation de la Recherche Médicale (Paris). L. Vincent was supported by a grant from the French Ministère de la Recherche. The authors thank the Laboratory of Pharmacology at the CHSA for measurements of plasma concentrations. The authors declare that they have no conflict of interest.

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  1. Laboratoire de Neurobiologie et Pharmacologie Moléculaire, Centre de Psychiatrie et Neurosciences (CPN, U 894), INSERM, 2 ter rue d’Alésia, 75014, Paris, France

    Marie Humbert-Claude, Elisabeth Davenas, Florence Gbahou, Ludwig Vincent & Jean-Michel Arrang

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  1. Marie Humbert-Claude
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  2. Elisabeth Davenas
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  3. Florence Gbahou
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  4. Ludwig Vincent
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  5. Jean-Michel Arrang
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Correspondence to Jean-Michel Arrang.

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Humbert-Claude, M., Davenas, E., Gbahou, F. et al. Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo. Psychopharmacology 220, 225–241 (2012). https://doi.org/10.1007/s00213-011-2471-5

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  • DOI: https://doi.org/10.1007/s00213-011-2471-5

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