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

• DOI: 10.1016/j.neuroscience.2008.09.042
• Publication Date: 2008-10-02T09:11:04Z
• Authors: N. Ito; T. Yabe; Y. Gamo; T. Nagai; T. Oikawa; H. Yamada; T. Hanawa
• Keywords: Male; 0301 basic medicine; Analysis of Variance; Benzoxazoles; Doublecortin Protein; Dose-Response Relationship, Drug; Neurogenesis; Intracellular Signaling Peptides and Proteins; Immobility Response, Tonic; Nerve Tissue Proteins; Embryo, Mammalian; Hippocampus; 3. Good health; Mice; 03 medical and health sciences; Bromodeoxyuridine; Exploratory Behavior; Animals; Neuropeptide Y; Naphthyridines; Cells, Cultured; Cell Proliferation; Injections, Intraventricular

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.