Modulation of the firing activity of female dorsal raphe nucleus serotonergic neurons by neuroactive steroids.
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.
Robichaud
M
M
Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
Debonnel
G
G
D043582:5-alpha-Dihydroprogesterone / Q000494:pharmacology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D005783:Gender Identity; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D011284:Pregnenolone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
D000840:Anisoles; D014150:Antipsychotic Agents; D012739:Gonadal Steroid Hormones; D011437:Propylamines; D020033:Protein Isoforms; D017480:Receptors, sigma; D013196:Dihydrotestosterone; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D012701:Serotonin; D003687:Dehydroepiandrosterone; D011374:Progesterone; D018120:Finasteride; D011284:Pregnenolone; D043582:5-alpha-Dihydroprogesterone; C009954:trilostane