Regulation of 5-HT receptors by corticosteroids: where do we stand?

Twenty five years ago, experimental procedures such as adrenalectomy and corticosteroid administration (to intact rats) allowed the recognition of direct and indirect controls of central 5-HT synthesis rate by corticosteroids. These effects indicated that the activity of the hypothalamo-pituitary-adrenal (HPA) axis, whether under basal conditions or during stress, is endowed with a modulatory action upon serotonergic neurons. Nowadays, in situ hybridisation, in vitro autoradiography, and radioligand binding on the one hand, and electrophysiological, behavioural, and neuroendocrinological responses on the other hand, are tools that allow the analysis of direct corticosteroid effects upon 5-HT receptors. Among the dozen of 5-HT receptors identified so far, four receptors (namely the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C receptors)--and the 5-HT uptake system--have been the focus of studies aimed at detecting corticosteroid modulatory effects. The results that are reviewed herein indicate that hippocampal 5-HT1A receptors are under the tonic inhibitory control of corticosterone. This control is directly exerted at the level of the 5-HT1A receptor gene, essentially through mineralocorticoid receptors; as well, electrophysiological findings bring support for an additional modulation of hippocampal 5-HT1A receptor-mediated functions by indirect (ie 5-HT1A receptor gene-independent) genomic actions of corticosteroids. In keeping with the respective effects of stressful stimuli and psychotropic drugs upon the HPA axis and central serotonergic systems, it is likely that these corticosteroid-5-HT1A receptor interactions in the hippocampus have consequences in the pathophysiology of mood disorders. However, because the data regarding a corticosteroid control of other 5-HT receptors are either scarce and contradictory (eg 5-HT1B, 5-HT2A, 5-HT2C receptors and 5-HT uptake systems) or lacking, it is at the present time unknown whether corticosteroids exert other effects on 5-HT receptor-mediated functions, including those related to homeostasis.