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Abstract
Serotonin and glucocorticoids interact at the hippocampus to alter neuronal function.
Serotonin and antidepressant drugs increase glucocorticoid receptor and mineralocorticoid
receptor gene expression in hippocampal neurons over a few days. The effects of serotonin
are mediated via ketanserin-sensitive "serotonin-2 type" receptors and induction of
cyclic AMP, although the subsequent molecular mechanisms are unclear. Recently, we
have shown that chronic environmental manipulations which induce glucocorticoid receptor
gene expression in specific hippocampal subfields of the rat are associated with congruent
induction of the transcription factor NGFI-A (zif268, krox24, egr-1) and repression
of AP-2; both factors may bind to the glucocorticoid receptor gene promoter. However,
any relationship between serotonin and these transcription factors is unknown. Here,
we show that acute restraint stress, which causes serotonin release at the hippocampus,
induces hipppocampal NGFI-A, but represses activator protein-2 and mineralocorticoid
receptor 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 also the fall in AP-2 messenger RNA expression.
These data suggest that restraint stress, acting via serotonin release and ketanserin-sensitive
serotonin receptors, produces rapid, transient and specific changes in transcription
factor gene expression in hippocampal neurons. Any link between these effects and
the control of glucocorticoid and mineralocorticoid receptor expression with chronic
serotonin or antidepressant treatment remains to be elucidated.