1. ¹Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV, USA
2. ²Department of Physiology and Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA
3. ³Department of Neurobiology and Anatomy, West Virginia University Health Sciences Center, Morgantown, WV, USA

Correspondence: Dr H-T Zhang, Department of Behavioral Medicine and Psychiatry, West Virginia University Health Sciences Center, Morgantown, WV 26506-9137, USA. Tel: 304 293 1488, Fax: 304 293 1634, E-mail: hzhang@hsc.wvu.edu

⁴Present address: Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

Received 29 December 2008; Revised 29 April 2009; Accepted 2 May 2009; Published online 10 June 2009.

Abstract

Inhibition of phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP (cAMP), increases phosphorylation of the cAMP response element binding protein (pCREB) and hippocampal neurogenesis, and produces antidepressant-like effects on behavior; however, causal links among these actions have not been established. In this study, chronic administration of rolipram (0.31–1.25 mg/kg, 16–23 days) produced antidepressant- and anxiolytic-like effects on behavior in mice. It also increased cAMP and pCREB levels in the hippocampus and prefrontal cortex, but increased Sox2, a marker for mitotic progenitor cells, only in the hippocampus. Chronic rolipram treatment also increased hippocampal neurogenesis, as evidenced by increased bromodeoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus. Methylazoxymethanol (MAM), which is toxic to proliferating cells, reversed rolipram-induced increases in BrdU-positive cells and pCREB in the hippocampus and partially blocked its behavioral effects. Approximately 84% of BrdU-positive cells became newborn neurons, 93% of which co-expressed pCREB; these proportions were not altered by rolipram or MAM, either alone or in combination. Finally, 3 weeks after the end of the MAM treatment, when neurogenesis was no longer inhibited, rolipram again increased hippocampal pCREB and its antidepressant- and anxiolytic-like effects were restored. Overall, these results suggest that rolipram produces its effects on behavior in a manner that at least partially depends on its neurogenic action in the hippocampus, targeting mitotic progenitor cells rather than newborn or mature neurons; cAMP/CREB signaling in hippocampal newborn neurons is critical for neurogenesis and contributes to the behavioral effects of rolipram.