Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids

Abstract

Important gender differences in mood disorders result in a greater susceptibility for women. Accumulating evidence suggests a reciprocal modulation between the 5-hydroxytryptamine (5-HT) system and neuroactive steroids. Previous data from our laboratory have shown that during pregnancy, the firing activity of 5-HT neurons increases in parallel with progesterone levels. This study was undertaken to evaluate the putative modulation of the 5-HT neuronal firing activity by different neurosteroids. Female rats received i.c.v. for 7 days a dose of 50 μ g/kg per day of one of the following steroids: progesterone, pregnenolone, 5β-pregnane-3,20-dione (5β-DHP), 5β-pregnan-3α-ol,20-one, 5β-pregnan-3β-ol,20-one, 5α-pregnane-3,20-dione, 5α-pregnan-3α-ol,20-one (allopregnanolone, 3α,5α-THP), 5α-pregnane-3β-ol,20-one and dehydroepiandrosterone (DHEA). 5β-DHP and DHEA were also administered for 14 and 21 days (50 μg/kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 (σ1) receptor antagonist NE-100. In vivo, extracellular unitary recording of 5-HT neurons performed in the dorsal raphe nucleus of these rats revealed that DHEA, 5β-DHP and 3α,5α-THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5β-DHP and DHEA showed different time-frames for their effects with 5β-DHP having its greatest effect after 7 days to return to control values after 21 days, whereas DHEA demonstrated a sustained effect over the 21 day period. NE-100 prevented the effect of DHEA but not of 5β-DHP, thus indicating that its σ1 receptors mediate the effect of DHEA but not that of 5β-DHP. In conclusion, our results offer a cellular basis for potential antidepressant effects of neurosteroids, which may prove important particularly for women with affective disorders. © 2004 Society for Endocrinology.