Fluoxetine-induced proliferation and differentiation of neural progenitor cells isolated from rat postnatal cerebellum

Biochem Pharmacol. 2008 Aug 1;76(3):391-403. doi: 10.1016/j.bcp.2008.05.014. Epub 2008 May 23.

Abstract

Previous studies have shown that the serotonin-reuptake inhibitor (SSRI) fluoxetine affects neural progenitors derived from postnatal cerebellum or adult hippocampus and stimulates their proliferation. In the human cerebellum, the proliferation of cerebellar granule cells (CGC) continues until the 11th postnatal month and could be influenced in infants by breastfeeding-delivered SSRIs. Current information about fluoxetine effects on postnatal cerebellar neural progenitors is limited. Here we report the characterization of fluoxetine actions on rat postnatal cerebellar neural progenitors. RT-PCR and immunostaining revealed the expression of serotonin transporter (SERT), 5HT(1A) receptors, tryptophan hydroxylase (TPH), and serotonin (5HT). Protracted in vitro fluoxetine treatment increased cell proliferation and differentiation. The proliferative effects of fluoxetine, 5HT, and the selective agonist of 5HT(1A) receptors trans-8-hydroxy-2-(N-n-propyl-N-3'-iodo-2'-propenyl)aminotetralin (8-OH-PIPAT) were abolished by the selective antagonist of 5HT(1A) receptors, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635). Furthermore, fluoxetine-induced activation of both the cAMP-response element-binding (CREB) protein and extracellular signal-regulated protein kinases (ERK1/2), which was abolished by the selective inhibitor of MAP kinase kinase (MEK) 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene (U0126), and increased cyclin D1 expression. All these effects were prevented by WAY-100635. Collectively, our results demonstrate that rat postnatal cerebellum contains neural progenitors capable of proliferating and differentiating in response to fluoxetine exposure, possibly through the activation of 5HT(1A) receptors. The relevance of these findings for possible SSRI effects on the developing postnatal/infant human cerebellum should be explored.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Cerebellum* / cytology
  • Cerebellum* / drug effects
  • Cerebellum* / growth & development
  • Dose-Response Relationship, Drug
  • Fluoxetine / pharmacology*
  • Immunohistochemistry
  • Neurons / cytology
  • Neurons / drug effects*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin Uptake Inhibitors / pharmacology*
  • Stem Cells / cytology
  • Stem Cells / drug effects*

Substances

  • RNA, Messenger
  • Receptors, Serotonin
  • Serotonin Uptake Inhibitors
  • Fluoxetine