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Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists

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Abstract

Rationale

H3-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.

Objectives

We further explored the effect of maximal doses (3–10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H3-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine.

Results

Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5–10 mg/kg). Low to moderate doses of haloperidol (0.1–0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine.

Conclusions

Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H3-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H3-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.

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Acknowledgments

This study was supported by INSERM and the French Ministère de la Recherche. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratoire de Neurobiologie et Pharmacologie Moléculaire, INSERM/Université Paris Descartes, 2 ter rue d’Alésia, 75014, Paris, France

    Aude Burban, Chit Sadakhom, Dominique Dumoulin, Christiane Rose, Henriette Frances & Jean-Michel Arrang

  2. Laboratoire de Physiopathologie des Maladies Psychiatriques, INSERM/Université Paris Descartes, U894, Paris, France

    Gwenaëlle Le Pen

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  1. Aude Burban
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Burban, A., Sadakhom, C., Dumoulin, D. et al. Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists. Psychopharmacology 210, 591–604 (2010). https://doi.org/10.1007/s00213-010-1863-2

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