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Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme

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Abstract

Rationale

Phosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (cAMP) by catalyzing its hydrolysis. Four separate PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. PDE4 has been reported to be involved in various central nervous system (CNS) functions including depression, memory, and schizophrenia, although the specific subtype mediating these effects remains unclear.

Objective

To investigate the role of PDE4B in the CNS, PDE4B wild-type and knockout mice (C57BL/6N background) were assessed in a variety of well-characterized behavioral tasks, and their brains were assayed for monoamine content.

Results

Knockout mice showed a significant reduction in prepulse inhibition. Spontaneous locomotor activity was decreased (16%) in knockout mice. Furthermore, when challenged with amphetamine, both groups of mice responded similarly to a low dose of d-amphetamine (1.0 mg/kg), but knockout mice showed an enhanced response to a higher dose (1.78 mg/kg). Decreases in baseline levels of monoamines and their metabolites within the striatum of knockout mice were also observed. PDE4B knockout mice showed a modest decrease in immobility time in the forced swim test that approached significance. In several other tests, including the elevated plus maze, hot plate, passive avoidance, and Morris water maze, wild-type and knockout mice performed similarly.

Conclusion

The present studies demonstrate decreased striatal DA and 5-HT activity in the PDE4B knockout mice associated with decreased prepulse inhibition, decreased baseline motor activity, and an exaggerated locomotor response to amphetamine. These data further support a role for PDE4B in psychiatric diseases and striatal function.

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Abbreviations

DA:

dopamine

DOPAC:

dihydroxyphenlyacetic acid

5-HIAA:

5-hydroxyindoleacetic acid

5-HT:

serotonin

HVA:

homovanillic acid

PDEs:

phosphodiesterase

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Acknowledgment

The authors would like to thank Dr. Marco Conti for supplying the breeding pairs of PDE4B wild-type and knockout mice used to initiate our colonies, Linda Loverro for her assistance in the breeding, colony expansion, and delivery of the knockout mice, and Dr. John Kehne for helpful discussions during the preparation of this manuscript. Portions of this work were presented at the Society for Neuroscience Meeting, 2007.

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Authors and Affiliations

  1. CNS Discovery Research, Pfizer Global Research & Development, Groton, CT, 06340, USA

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

  2. Neuroscience, Bristol Myers Squibb, 5 Research Parkway, Wallingford, CT, 06492, USA

    Judith A. Siuciak

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  1. Judith A. Siuciak
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  2. Sheryl A. McCarthy
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  4. Ashley N. Martin
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Correspondence to Judith A. Siuciak.

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Siuciak, J.A., McCarthy, S.A., Chapin, D.S. et al. Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology 197, 115–126 (2008). https://doi.org/10.1007/s00213-007-1014-6

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