Regulation of central corticosteroid receptors following short-term activation of serotonin transmission by 5-hydroxy-L-tryptophan or fluoxetine.
Alterations of the hypothalamic-pituitary-adrenal (HPA) axis function characterized by a decreased negative feedback capacity are often associated with affective disorders and are corrected by treatment with antidepressant drugs. To gain a better understanding of the effects of the antidepressant drug fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on central corticosteroid receptors, the effects of short-term activation of serotonin transmission on central corticosteroid receptor expression were analysed in adrenalectomized (ADX) rats either supplemented or not with corticosterone. Serotonin transmission was stimulated either by a single injection of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), or by a 2-day treatment with fluoxetine. In ADX rats, administration of 5-HTP decreased hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor numbers 24 h later, while their respective mRNAs were unchanged and these effects of 5-HTP were mediated by 5-HT2 receptors. In the hypothalamus, GR mRNAs and binding sites decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetine treatment increased hippocampal MR and GR mRNAs and MR binding sites while GR number remained unchanged. In ADX rats supplemented with corticosterone, 5-HTP and fluoxetine treatment had the same effects on corticosteroid receptors compared to those observed in non supplemented ADX rats: 5-HTP decreased hippocampal MR and GR and hypothalamic GR while fluoxetine treatment increased hippocampal MR. These results show that short-term stimulation of 5-HT transmission by 5-HTP decreases hippocampal and hypothalamic corticosteroid receptor numbers through a corticosterone-independent mechanism. It is hypothesized that the delayed maximal increase in extracellular 5-HT contents after fluoxetine treatment, due to negative feedback regulations induced by the activation of 5-HT1A and 5-HT1B autoreceptors, is not the primary cause for the delayed normalization of corticosteroid receptor numbers that regulates the HPA axis functioning.
Laboratoire des Interactions fonctionnelles en Neuroendocrinologie, INSERM U501, Université de la Méditerranée, IFR Jean-Roche, UER de Médecine Nord, Marseille, France.
A
A
Sémont
M
M
Fache
F
F
Héry
M
M
Faudon
F
F
Youssouf
M
M
Héry
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000284:Administration, Oral; D000315:Adrenalectomy; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D003345:Corticosterone / Q000008:administration & dosage; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009778:Occipital Lobe / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D006916:5-Hydroxytryptophan; D003345:Corticosterone; D005473:Fluoxetine; D006897:Hydroxyindoleacetic Acid; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors