I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation

Neuroscience. 2008 Dec 10;157(4):720-32. doi: 10.1016/j.neuroscience.2008.09.042. Epub 2008 Oct 1.


A decrease in orexin-A (OX-A) levels has been reported to be associated with depression. It is also well known that stress and depression can disrupt neurogenesis in the dentate gyrus of the hippocampus; however, it is unclear how OX-A is involved in depression and/or neurogenesis. In the present study, we investigated the effect of i.c.v. administration of OX-A on the forced swimming test (FST), an accepted behavioral screen of antidepressant-like activity, and on the cell proliferation with bromodeoxyuridine (BrdU) in the dentate gyrus at 4 days after i.c.v. administration of OX-A. OX-A administration (140 pmol/mouse) led to a significant reduction in animal immobility in the FST, without affecting spontaneous locomotor activities or serum corticosterone levels. In addition, the number of BrdU-positive cells in the dentate gyrus was significantly increased in OX-A-treated mice in vivo; however, OX-A did not affect the percentage of doublecortin-positive cells in the dentate gyrus. The proliferation of neural progenitor cells derived from rat fetal brain was not affected by OX-A treatment in vitro, and the orexin receptor 1 (OXR1) protein was not expressed in these cells. Treatment with the OXR1 antagonist SB-334867 (30 mg/kg, i.p.) blocked both the OX-A-induced decrease in the immobility of FST and increase in BrdU-positive. Moreover, the OX-A-induced increase in neuropeptide Y (NPY)-positive cells in the hilus of the dentate gyrus was blocked by SB-334867. These results suggest that OX-A induces an antidepressive-like effect, at least in part, via the enhancement of cell proliferation in the dentate gyrus. These effects of OX-A also may be partly relevant to the regulation of the NPY system in the hilus of the dentate gyrus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Benzoxazoles / pharmacology
  • Bromodeoxyuridine / metabolism
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Doublecortin Protein
  • Embryo, Mammalian
  • Exploratory Behavior / drug effects
  • Hippocampus / drug effects*
  • Hippocampus / physiology
  • Immobility Response, Tonic / drug effects
  • Injections, Intraventricular / methods
  • Intracellular Signaling Peptides and Proteins / administration & dosage*
  • Male
  • Mice
  • Naphthyridines
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / drug effects
  • Neuropeptide Y / metabolism
  • Neuropeptides / administration & dosage*
  • Neurotransmitter Agents / administration & dosage*
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / metabolism
  • Stem Cells / drug effects
  • Urea / analogs & derivatives
  • Urea / pharmacology


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Benzoxazoles
  • Dcx protein, rat
  • Doublecortin Protein
  • Intracellular Signaling Peptides and Proteins
  • Naphthyridines
  • Nerve Tissue Proteins
  • Neuropeptide Y
  • Neuropeptides
  • Neurotransmitter Agents
  • Orexin Receptors
  • Orexins
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Urea
  • Bromodeoxyuridine