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 micro g/kg per day of one of the following steroids: progesterone, pregnenolone, 5beta-pregnane-3,20-dione (5beta-DHP), 5beta-pregnan-3alpha-ol,20-one, 5beta-pregnan-3beta-ol,20-one, 5alpha-pregnane-3,20-dione, 5alpha-pregnan-3alpha-ol,20-one (allopregnanolone, 3alpha,5alpha-THP), 5alpha-pregnane-3beta-ol,20-one and dehydroepiandrosterone (DHEA). 5beta-DHP and DHEA were also administered for 14 and 21 days (50 micro g/kg per day, i.c.v.) as well as concomitantly with the selective sigma 1 (sigma1) 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, 5beta-DHP and 3alpha,5alpha-THP significantly increased the firing activity of the 5-HT neurons. Interestingly, 5beta-DHP and DHEA showed different time-frames for their effects with 5beta-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 5beta-DHP, thus indicating that its sigma1 receptors mediate the effect of DHEA but not that of 5beta-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.
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G Debonnel, R Bergeron, and C de Montigny
We have previously shown in vivo that low doses of selective sigma (σ) receptor ligands potentiate selectively and dose-dependently the excitatory response of pyramidal neurons to microiontophoretic applications of N-methyl-d-aspartate (NMDA) in the CA3 region of the rat dorsal hippocampus. As several neuroactive steroids such as progesterone and testosterone have a high affinity for σ receptors, the effects of some neuroactive steroids on the NMDA-induced neuronal response were assessed using extracellular unitary recordings of CA3 dorsal hippocampus pyramidal neurons obtained in anesthetized Sprague-Dawley rats.
Low doses of dehydroepiandrosterone (DHEA) potentiated selectively and dose-dependently the NMDA response without affecting those to acetylcholine or quis-qualate. This potentiating effect of DHEA was suppressed by the selective σ1 antagonist NE-100 and by the non-selective σ antagonist haloperidol. Low doses of progesterone and of testosterone did not modify the NMDA response, but reversed the potentiating effects of DHEA as well as those of the non-steroidal σ ligands di-tolyl-guanidine (DTG), (+)pentazocine and JO-1784. The two neuroactive steroids with a low affinity for σ receptors, pregnenolone and pregnenolone sulfate, had no effect on the NMDA response, and did not modify the potentiation of the NMDA response induced by DHEA and by non-steroidal σ ligands. The potentiation of the NMDA response by DTG (1 μ/kg i.v.) was significantly greater in ovariectomized rats than in males and non-ovariectomized females on either day one or three of the estrous cycle.
These results suggest that some neuroactive steroids such as DHEA, progesterone and testosterone modulate the NMDA response via σ receptors. Furthermore, they also indicate that endogenous progesterone and testosterone, by acting as non-selective σ antagonists, may produce a tonic dampening of the function of σ receptors and consequently a decrease in the NMDA receptor function.
Journal of Endocrinology (1996) 150, S33–S42