Serotonergic 5-HT2A receptor stimulation induces steroid 5α-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive mood disorders and well known to inhibit the reuptake of neurotransmitter serotonin into nerve terminals. Thus, it seems conceivable that these drugs may induce the outflow of serotonin from the synapse as a consequence of inhibiting the reuptake, resulting in the stimulation of glial cells surrounding nerve terminals. On this hypothesis, the effect of serotonin on steroid 5α-reductase type 1 (5α-R) gene expression in rat C6 glioma cells was examined as one of the in vitro model experiments for investigating the indirect influence of SSRIs on glial cells. Serotonin elevated 5α-R mRNA and protein levels through the stimulation of serotonin 5-HT_2A receptors, and also elevated Egr-1 mRNA and protein levels prior to 5α-R gene expression in the glioma cells. Furthermore, serotonin failed to significantly increase 5α-R mRNA levels in the cells preloaded with the antisense oligodeoxynucleotide targeted on Egr-1 gene. These results indicate that serotonin may stimulate 5α-R gene expression via transcription factor Egr-1 in glial cells, thus suggesting that serotonin flowing out of the serotonergic synapse may be implicated in SSRI-induced changes in neurosteroid metabolism in brain.