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H3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval

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Abstract

Rationale

Accumulated evidence suggests a role for histamine in cognition and the use of H3 receptor antagonists in the treatment of learning and memory disorders.

Objectives

The aim of the current study was to investigate the cognition enhancing properties of ciproxifan, an H3 receptor antagonist, after natural forgetting in normal adult rats.

Materials and methods

The novel object discrimination task, a recognition memory test based on spontaneous exploratory behaviour, was used. Briefly, rats exposed to two identical objects during an acquisition trial can discriminate between a novel object and a familiar one during a subsequent choice trial after a short delay but not after a 24-h inter-trial interval.

Results

The scopolamine (0.5 mg/kg, i.p.)-induced impairment after a short delay was abolished by ciproxifan (p < 0.001). Natural forgetting was prevented by a single administration of ciproxifan (3 mg/kg) prior to the retention test (p < 0.001) but not when administered before or immediately after the acquisition trial (schedule effect p < 0.05), demonstrating a specific activity on memory retrieval. Pretreatment with either pyrilamine (10 mg/kg), an H1 antagonist, or zolantidine (10 mg/kg), an H2 antagonist, prevented the retrieval enhancement effect of ciproxifan (p < 0.05 and p < 0.001, respectively).

Conclusions

Histamine H3 receptor antagonists restore the performance of rats impaired by scopolamine and enhance recognition memory after acute administration before the retrieval phase via a mechanism dependent on H1 and H2 receptor activation.

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Acknowledgements

Thanks are due to Dominique Schweizer from the Cephalon France Medicinal Chemistry Department who synthesised ciproxifan. Thanks to View Point for developing the video monitoring system used in the NOD task with us. Cephalon Inc. supported this study. We are also grateful to Peter Vanhoutte, Denis Hervé, Jocelyne Caboche, Donna Bozyczko-Coyne, Christopher Heath and Michael Williams for the critical reading of the manuscript. Experiments were done in strict compliance with the recommendations of the EEC (86/609/CEE) for the care and use of laboratory animals and were approved by the Animal Care Committee of Cephalon France.

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  1. Vincent Pascoli

    Present address: Laboratoire Signalisation Neuronale et Régulations géniques CNRS-UMR7102, Université Pierre et Marie Curie, Paris VI, France

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  1. Pharmacologie du Système Nerveux Central, Centre de Recherches de Cephalon, Maisons-Alfort, France

    Corinne Boer-Saccomani & Jean-François Hermant

  2. 9 Quai Saint bernard, Bâtiment B, 6ième étage, 75005, Paris, France

    Vincent Pascoli

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  1. Vincent Pascoli
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Pascoli, V., Boer-Saccomani, C. & Hermant, JF. H3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval. Psychopharmacology 202, 141–152 (2009). https://doi.org/10.1007/s00213-008-1171-2

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