Abstract
Rationale
Phosphodiesterases (PDEs) are a super family of enzymes responsible for the halting of intracellular cyclic nucleotide signaling and may represent novel therapeutic targets for treatment of cognitive disorders. PDE4 is of considerable interest to cognitive research because it is highly expressed in the brain, particularly in the cognition-related brain regions. Recently, the functional role of PDE4B and PDE4D, two of the four PDE4 subtypes (PDE4A, B, C, and D), in behavior has begun to be identified; however, the role of PDE4A in the regulation of behavior is still unknown.
Objectives
The purpose of this study was to characterize the functional role of PDE4A in behavior.
Methods
The role of PDE4A in behavior was evaluated through a battery of behavioral tests using PDE4A knockout (KO) mice; urine corticosterone levels were also measured.
Results
PDE4A KO mice exhibited improved memory in the step-through-passive-avoidance test. They also displayed anxiogenic-like behavior in elevated-plus maze, holeboard, light–dark transition, and novelty suppressed feeding tests. Consistent with the anxiety profile, PDE4A KO mice had elevated corticosterone levels compared with wild-type controls post-stress. Interestingly, PDE4A KO mice displayed no change in object recognition, Morris water maze, forced swim, tail suspension, and duration of anesthesia induced by co-administration of xylazine and ketamine (suggesting that PDE4A KO may not be emetic).
Conclusions
These results suggest that PDE4A may be important in the regulation of emotional memory and anxiety-like behavior, but not emesis. PDE4A could possibly represent a novel therapeutic target in the future for anxiety or disorders affecting memory.
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Acknowledgements
This work was supported by research grants from the NARSAD Young Investigator Award [1008640 for 2006, and 10011226 for 2008 to H.T. Zhang], and the National Institute on Aging [AG031687 to H.T. Zhang]. We would like to thank Dr. James O’Donnell for his guidance and use of laboratory materials necessary for this research to be performed; Dr. James O’Callaghan for the assistance and use of his microwave fixation machine; Dr. Rae Matsumoto for the use of her PAS automated open field chambers; and Dr. Max Sokolov for the use of his Licor Odyssey Infrared Imaging Scanner.
Conflicts of interest
Han-Ting Zhang is the scientific consultant of Asubio Pharmaceuticals and Takeda Pharmaceuticals; he has received financial support for his research from Lundbeck Pharmaceuticals. None of the companies sold any drugs or devices mentioned in the article. The other authors have no financial interests to disclose.
Support and potential conflict
This work was supported by research grants from the NARSAD Young Investigator Award [1008640 for 2006 and 10011226 for 2008 to H.T. Zhang] and the National Institute on Aging [AG031687 to H.T. Zhang]. Han-Ting Zhang is the scientific consultant of Asubio Pharmaceuticals and Takeda Pharmaceuticals; he has received financial support for his research from Lundbeck Pharmaceuticals. None of the companies sold any drugs or devices mentioned in the article. The other authors have no financial interests to disclose.
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Hansen, R.T., Conti, M. & Zhang, HT. Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior. Psychopharmacology 231, 2941–2954 (2014). https://doi.org/10.1007/s00213-014-3480-y
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DOI: https://doi.org/10.1007/s00213-014-3480-y