1. ¹Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV, USA
2. ²Department of Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, WV, USA
3. ³Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
4. ⁴Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University School of Medicine, Stanford, CA, USA

Correspondence: Dr H-T Zhang, Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, 1 Medical Center Dr., Morgantown, WV 26506, USA. Tel: +1 304 293 1488; Fax: +1 304 293 1634; E-mail: hzhang@hsc.wvu.edu

Received 2 March 2007; Revised 14 July 2007; Accepted 16 July 2007; Published online 15 August 2007.

Abstract

Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B- /- ). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B- /- mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B- /- mice. Compared to PDE4B+/+ littermates, PDE4B- /- mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B- /- mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B- /- mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B- /- mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.