Chronic treatment with antidepressant drugs (2 weeks or longer) increases corticosteroid receptor mRNA expression in the hippocampus and reduces hypothalamic-pituitary-adrenal axis activity in parallel with improving mood and neuroendocrine function. Earlier effects are less well documented. We examined the effects of short term (9 days) treatment with fluoxetine (10 mg/kg) and venlafaxine (10 mg/kg) on hippocampal mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) mRNA expression and spatial memory in adult rats. In situ hybridization histochemistry showed that the antidepressants decreased MR mRNA expression in all hippocampal subregions (e.g. 45% decrease in CA1 with venlafaxine, P<0.001), while GR mRNA expression was selectively reduced in the CA3 subregion. There was a trend for decreased plasma corticosterone levels following fluoxetine (50% fall, P=0.07) and venlafaxine (30% fall, P=0.18) but neither antidepressants affected spatial memory in the watermaze. Thus antidepressants can have complex and opposing actions on hippocampal corticosteroid receptor expression depending on the duration of treatment.