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Anxiolytic‐like effect of the PDE4 inhibitor rolipram and its relationship to cAMP signaling and hippocampal neurogenesis
Author(s) -
Li YunFeng,
Huang Ying,
Stolinski Lisa R,
O'Donnell James M,
Zhang HanTing
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.904.12
Subject(s) - rolipram , neurogenesis , anxiolytic , creb , dentate gyrus , hippocampal formation , endocrinology , medicine , anxiogenic , chemistry , phosphodiesterase , hippocampus , neuroscience , pharmacology , psychology , biology , receptor , biochemistry , enzyme , transcription factor , gene
Phosphodiesterase‐4 (PDE4), an enzyme that hydrolyzes cyclic AMP (cAMP), plays a critical role in controlling intracellular cAMP concentrations. Since cAMP signaling regulates anxiety, it was of interest to know if PDE4 was involved in anxiety‐like behavior. In behavioral tests sensitive to anxiolytic drugs, including elevated‐plus maze, light‐dark transition, and holeboard tests, chronic treatment with the PDE4 inhibitor rolipram (1.25 mg/kg, 17–21 d) produced anxiolytic‐like effects in mice and increases in cAMP and phospho‐CREB (pCREB) in both the hippocampus and prefrontal cortex and hippocampal neurogenesis (i.e., increased BrdU‐positive cells in the dentate gyrus). In addition, the effects of rolipram on hippocampal pCREB and neurogenesis were concurrently blocked by methylazoxymethanol (MAM, 5 mg/kg, 14 d), a toxin to proliferation cells; its anxiolytic‐like effect also was attenuated by MAM in a parallel pattern. Further, the inhibitory effects of MAM disappeared 19 d after MAM withdrawal. Finally, the effects of rolipram and/or MAM on BrdU‐labeled cells, pCREB, and behavior were highly correlated with each other. These results suggest that 1) PDE4 is involved in the regulation of anxiety‐like behavior; 2) cAMP/CREB signaling plays an important role in anxiolytic‐like and neurogenic effects of rolipram; 3) rolipram‐induced neurogenesis contributes to its anxiolytic activity.