Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat.
The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter's reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.
Pinnock
S B
SB
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Lazic
S E
SE
Wong
H T
HT
Wong
I H W
IH
Herbert
J
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D053687:Adult Stem Cells / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D003345:Corticosterone; D003687:Dehydroepiandrosterone; D005473:Fluoxetine; D019394:Ki-67 Antigen; D017367:Selective Serotonin Reuptake Inhibitors