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.
Sémont
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Laboratoire des Interactions fonctionnelles en Neuroendocrinologie, INSERM U501, Université de la Méditerranée, IFR Jean-Roche, UER de Médecine Nord, Marseille, France.
Fache
M
M
Héry
F
F
Faudon
M
M
Youssouf
F
F
Héry
M
M
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