The role of 5-HT1A receptors in the proliferation and survival of progenitor cells in the dentate gyrus of the adult hippocampus and their regulation by corticoids

Neuroscience. 2005;135(3):803-13. doi: 10.1016/j.neuroscience.2005.05.056. Epub 2005 Aug 29.

Abstract

These experiments explore the role of 5-HT1A receptors in the regulation of cell proliferation in the dentate gyrus of the intact and adrenalectomized adult rat. Depleting 5-HT with p-chlorophenylalanine (300 mg/kg initially followed by 100 mg/kg/day) or stimulating 5-HT1A receptors with 8-OH-DPAT (1 mg/kg or 2 mg/kg, s.c. injections twice daily) for 14 days had no effect on cell proliferation as measured by Ki-67 or BrdU (5-bromo-3-deoxyuridine) immunocytochemistry in the dentate gyrus. However, combined treatment with p-chlorophenylalanine followed by 8-OH-DPAT significantly increased cell proliferation compared with p-chlorophenylalanine alone. Micro-injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine into the fimbria-fornix (3.0 microg/side) and the cingulate bundle (1.8 microg/side) depleted hippocampal 5-HT locally but did not change cell proliferation 3 weeks after the surgery. However, 8-OH-DPAT (1 mg/kg, twice daily) stimulated cell proliferation in the dentate gyrus of hippocampal 5-HT-depleted rats compared with controls. These results suggest that 5-HT(1A) modulates cell proliferation in the hippocampus by a direct post-synaptic effect. Previous studies demonstrate that adrenalectomy increases hippocampal 5-HT1A receptor expression and binding, and thus we investigated whether the effect of adrenalectomy on cell proliferation and survival was dependent on the activity of the 5-HT1A receptors. In contrast to the null effect following twice-daily s.c. injection, 8-OH-DPAT (2.0 mg/kg/day) delivered by s.c. osmotic pumps increased proliferation in intact rats. The 5-HT1A antagonist WAY-100635 (1.5 mg/kg/day also delivered by osmotic pump) by itself did not alter cell proliferation, confirming that reduced serotonin activity does not change proliferation, but blocked the effect of 8-OH-DPAT. However, WAY-100635 could not block the stimulating action of adrenalectomy cell proliferation. 5-HT1A mRNA expression was not altered in the hippocampus by adrenalectomy. Thus, the effect of adrenalectomy on cell proliferation and survival is not 5-HT1A dependent, despite the interaction between 5-HT1A and corticosterone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5,7-Dihydroxytryptamine / pharmacology
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Adrenal Cortex Hormones / pharmacology*
  • Adrenalectomy
  • Animals
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Corticosterone / metabolism
  • Dentate Gyrus / cytology*
  • Dentate Gyrus / drug effects
  • Immunohistochemistry
  • In Situ Hybridization
  • Ki-67 Antigen / pharmacology
  • Male
  • Rats
  • Receptor, Serotonin, 5-HT1A / drug effects*
  • Serotonin Agents / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Stem Cells / drug effects*
  • Tissue Fixation

Substances

  • Adrenal Cortex Hormones
  • Ki-67 Antigen
  • Serotonin Agents
  • Serotonin Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • 5,7-Dihydroxytryptamine
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Corticosterone