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

Details

• Personal Author:
  O'Callaghan JP ; O'Donnell JM ; Xiao L
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Cell Division Drug Therapy Enzymes Laboratories Nervous System Occupational Health Pharmacies Pyridines Safety
• Keywords:
  Animal-studies Brain-function Brain-matter Cell-division Cell-function Cell-transformation Dose-response Drug-therapy Drugs Enzyme-inhibitors Laboratory-animals Laboratory-techniques Laboratory-testing Pharmacists Protein-biochemistry Proteins Therapeutic-agents

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• ISSN:
  0022-3565
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  338
• Issue:
  2
• NIOSHTIC Number:
  nn:20039234
• Citation:
  J Pharmacol Exp Ther 2011 Aug; 338(2):641-647
• Contact Point Address:
  L. Xiao, Medical Center Director, West Virginia University, HSC N 4028, Morgantown, WV 26506 USA
• Email:
  lxiao@hsc.wvu.edu
• Federal Fiscal Year:
  2011
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Pharmacology and Experimental Therapeutics
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:80c40a0a6bf587899aaecaa1bf67a871a8d82ee7a800d5427e6521c9e7c9893b2411b68281c1089ecb3650c85b02af239deb0101d5daf8ad1e0c10249aa2f029
• Download URL:
  https://stacks.cdc.gov/view/cdc/192650/cdc_192650_DS1.pdf
• File Type:
  [PDF - 1.06 MB ]