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 chara cterized by a decreased negative feedback capacity are often associated wit h affective disorders and are corrected by treatment with antidepressant dr ugs. To gain a better understanding of the effects of the antidepressant dr ug fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on central c orticosteroid 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 wi th fluoxetine. In ADX rats, administration of 5-HTP decreased hippocampal m ineralocorticoid (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 sit es decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetin e treatment increased hippocampal MR and GR mRNAs and MR binding sites whil e GR number remained unchanged. In ADX rats supplemented with corticosteron e, 5-HTP and fluoxetine treatment had the same effects on corticosteroid re ceptors compared to those observed in non supplemented ADX rats: 5-HTP decr eased 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 corticos teroid receptor numbers through a corticosterone-independent mechanism. It is hypothesized that the delayed maximal increase in extracellular 5-HT con tents after fluoxetine treatment, due to negative feedback regulations indu ced by the activation of 5-HT1A and 5-HT1B autoreceptors, is not the primar y cause for the delayed normalization of corticosteroid receptor numbers th at regulates the HPA axis functioning.