KETANSERIN SELECTIVELY BLOCKS ACUTE STRESS-INDUCED CHANGES IN NGFI-A AND MINERALOCORTICOID RECEPTOR GENE-EXPRESSION IN HIPPOCAMPAL-NEURONS

Serotonin and glucocorticoids interact at the hippocampus to alter neu ronal function. Serotonin and antidepressant drugs increase glucccorti coid receptor and mineralocorticoid receptor gene expression in hippoc ampal neurons over a few daps. The effects of serotonin are mediated v ia ketanserin-sensitive ''serotonin-2 type'' receptors and induction o f cyclic A-MP, although the subsequent molecular mechanisms are unclea r. Recently, we have shown that chronic environmental manipulations wh ich induce glucocorticoid receptor gene expression in specific hippoca mpal subfields of the rat are associated with congruent induction of t he transcription factor NGFI-A (zif268. krox24, egr-1) and repression of AP-2; both factors may bind to the glucocorticoid receptor gene pro moter. However, any relationship between serotonin and these transcrip tion factors is unknown. Here. we show that acute restraint stress, wh ich causes serotonin release at the hippocampus, induces hipppocampal NGFI-A, but represses activator protein-2 and mineralocorticoid recept or gene expression within 90 min. These changes are sustained for 4 h, but not 12 h. Ketanserin attenuates the stress-induced rise in NGFI-A and fall in mineralocorticoid receptor gene expression, and partly al so the fall in AP-2 messenger RNA expression. These data suggest that restraint stress, acting via serotonin release and ketanserin-sensitiv e serotonin receptors, produces rapid, transient and specific changes in transcription factor gene expression in hippocampal neurons. Any li nk between these effects and the control of glucocorticoid and mineral ocorticoid receptor expression with chronic serotonin or antidepressan t treatment remains to be elucidated. Copyright (C) 1996 IBRO.