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Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme

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Abstract

Rationale

Recent studies provide evidence for reduced phosphodiesterase-4B (PDE4B) as a genetic susceptibility factor as well as suggesting an association of several single nucleotide polymorphisms (SNPs) in PDE4B that are associated with an increased incidence of schizophrenia.

Objectives

The aim of the current study was to assess the activity of rolipram, a nonsubtype-selective PDE4 inhibitor, in several animal models predictive of antipsychotic-like efficacy and side-effect liability and to use PDE4B wild-type and knockout mice to begin to understand the subtypes involved in the activity of rolipram.

Results

In rats, rolipram antagonized both phencyclidine hydrochloride- and d-amphetamine-induced hyperactivity and inhibited conditioned avoidance responding (CAR). In PDE4B wild-type mice, rolipram dose-dependently suppressed CAR (ED50 = 2.4 mg/kg); however, in knockout mice, their sensitivity to rolipram at the higher doses (1.0 and 3.2 mg/kg) was reduced, resulting in a threefold shift in the ED50 (7.3 mg/kg), suggesting PDE4B is involved, at least in part, with the activity of rolipram. Only the highest dose of rolipram (3.2 mg/kg) produced a modest but significant degree of catalepsy.

Conclusions

Rolipram has a pharmacologic profile similar to that of the atypical antipsychotics and has low extrapyramidal symptom liability. These results suggest that PDE4B mediates the antipsychotic effects of rolipram in CAR and that the PDE4B-regulated cyclic adenosine monophosphate signaling pathway may play a role in the pathophysiology and pharmacotherapy of psychosis.

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Acknowledgments

The authors would like to thank Dr. Marco Conti for supplying the breeding pairs of PDE4B WT and KO mice used to initiate our colonies and Linda Loverro and the Genetically Modified Mice Group for their assistance in the breeding, colony expansion, and delivery of the knockout mice. Portions of this work were previously presented at the Society for Neuroscience Meeting, Atlanta, GA, October, 2006, and the International Congress on Schizophrenia Research, Colorado Springs, CO, April, 2007.

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  1. CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT, 06340, USA

    Judith A. Siuciak, Douglas S. Chapin, Sheryl A. McCarthy & Ashley N. Martin

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  1. Judith A. Siuciak
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  2. Douglas S. Chapin
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  3. Sheryl A. McCarthy
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Correspondence to Judith A. Siuciak.

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Siuciak, J.A., Chapin, D.S., McCarthy, S.A. et al. Antipsychotic profile of rolipram: efficacy in rats and reduced sensitivity in mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 192, 415–424 (2007). https://doi.org/10.1007/s00213-007-0727-x

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  • DOI: https://doi.org/10.1007/s00213-007-0727-x

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