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Effects of repeated treatment with phosphodiesterase-4 inhibitors on cAMP signaling, hippocampal cell proliferation, and behavior in the forced-swim test.

Authors
Xiao-L; O'Callaghan-JP; O'Donnell-JM
Source
J Pharmacol Exp Ther 2011 Aug; 338(2):641-647
NIOSHTIC No.
20039234
Abstract
The effects of repeated treatment with the phosphodiesterase-4 (PDE4) inhibitors rolipram, piclamilast, and 4-(2-(3-(cyclopentyloxy)- 4-methoxyphenyl)-2-phenylethyl) pyridine (CDP840), which differ in their interactions with high-and low-affinity binding conformers of the enzyme, were contrasted to those of acute treatment on cAMP signaling, hippocampal cell proliferation, and immobility in the forced-swim test in rats. Repeated treatment with rolipram (1 and 3 mg/kg), piclamilast (0.3 and 1 mg/kg), or CDP840 (10 and 30 mg/kg) for 16 days increased cAMP and phosphorylation of cAMP response element binding protein (pCREB) in hippocampus and prefrontal cortex. In addition, repeated treatment with the PDE4 inhibitors increased proliferation and survival of newborn cells in the hippocampus and produced antidepressant-like effects on behavior, as evidenced by decreased immobility in the forced-swim test. Acute treatment with rolipram (3 mg/kg), piclamilast (1 mg/kg), or CDP840 (30 mg/kg) induced transient increases in cAMP and pCREB in hippocampus and prefrontal cortex, but the dose and time dependence of these effects did not parallel the behavioral effects. Compared with rolipram and piclamilast, repeated treatment with CDP840 exerted lesser effects on neural and behavioral measures, probably because of its weak interaction with the high-affinity binding conformer of PDE4. This suggests the relative importance of the high-affinity binding conformer in the mediation of the long-term effects of PDE4 inhibition on cAMP/pCREB signaling, hippocampal cell proliferation, and antidepressant-like effects on behavior.
Keywords
Therapeutic-agents; Drug-therapy; Drugs; Pharmacists; Enzyme-inhibitors; Enzymes; Pyridines; Brain-function; Brain-matter; Cell-function; Cell-division; Cell-transformation; Protein-biochemistry; Proteins; Dose-response; Animal-studies; Animals; Laboratory-animals; Laboratory-techniques; Laboratory-testing
Contact
L. Xiao, Medical Center Director, West Virginia University, HSC N 4028, Morgantown, WV 26506 USA
CODEN
JPETAB
Publication Date
20110801
Document Type
Journal Article
Email Address
lxiao@hsc.wvu.edu
Fiscal Year
2011
NTIS Accession No.
NTIS Price
Issue of Publication
2
ISSN
0022-3565
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Journal of Pharmacology and Experimental Therapeutics
State
WV
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