Differential regulation of corticosteroid receptors by monoamine neurotransmitters and antidepressant drugs in primary hippocampal culture

Hyperactivity of the hypothalamic-pituitary-adrenal axis is a characteristic feature of depressive illness. The centrally located corticosteroid receptors, the glucocorticoid and mineralocorticoid receptors, are thought to be important modulators of this axis and changes in the levels of these receptors, particularly in the hippocampus, may underlie the hyperactivity observed. Various antidepressant drugs increase hippocampal mineralocorticoid and glucocorticoid receptor levels in vivo. These effects are thought to be mediated via alterations in monoaminergic neurotransmission. We examined whether serotonin (5HT) and noradrenaline (NA) have direct effects on glucocorticoid receptor and mineralocorticoid receptor expression in primary hippocampal neurones, and whether antidepressants also exert direct effects on target neurones. Exposure of hippocampal cells to 5HT for 4 days increased both glucocorticoid and mineralocorticoid receptor mRNA and protein expression. The induction of mineralocorticoid receptor mRNA was completely blocked by the 5HT₇ receptor antagonist SB 269970. In contrast glucocorticoid receptor induction was insensitive to the 5HT₇ receptor, whilst studies with the 5HT_1A receptor agonist 8-hydroxy-2-(di-n-proplamino) tetralin hydrochloride and the 5HT_1A receptor antagonist N-[2-[4-2-[O-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride (WAY 100635) suggest a partial role for 5HT_1A receptors in hippocampal glucocorticoid receptor regulation. Treatment with NA for 4 days also increased glucocorticoid receptor expression but had no effect on mineralocorticoid receptor expression. This was blocked by propanolol suggesting action via β-adrenergic receptors. Similarly to NA, fluoxetine and amitriptyline also selectively increased glucocorticoid receptor mRNA and protein levels over this time course. However, glucocorticoid receptor induction by fluoxetine or amitriptyline was not blocked by WAY 100635 or propanolol. These results show that 5HT, NA and antidepressants act directly but via distinct mechanisms on hippocampal neurones to regulate mineralocorticoid and glucocorticoid receptor expression. Thusly manipulation of neurotransmitter or antidepressant levels in the brain may aid in reversing hypothalamic-pituitary-adrenal axis hyperactivity by restoring hippocampal corticosteroid receptor balance.