Both glucocorticoids and serotonin have been implicated in the regulation of mood and neuroendocrine control. In this study we have examined the effects of the psychomotor stimulant, 3,4-methylenedioxymethamphetamine on corticosteroid and 5-hydroxytryptamine receptor subtype gene expression within the hippocampal formation using in situ hybridization histochemistry. Animals were injected subcutaneously with 3,4-methylenedioxymethamphetamine (20 mg/kg) twice daily for four days. Two weeks following this dosage regimen, shown to markedly reduce 5-hydroxytryptamine terminals, both glucocorticoid receptor and mineralocorticoid receptor messenger RNA expression were significantly decreased (30-47% fall) in the granule cells of the dentate gyrus and pyramidal cells of CA1-CA4 fields of Ammon's horn, but not in parietal cortex neurons. In the same rats, 5-hydroxytryptamine1C receptor messenger RNA expression was significantly increased in CA3 pyramidal neurons (133% rise), but neither 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptor messenger RNA levels were altered in any dorsal hippocampal subfield. 3,4-Methylenedioxymethamphetamine treatment was associated with modest hypersecretion of coricosterone during the diurnal nadir, without other peripheral evidence of chronic glucocorticoid excess (unchanged thymic and adrenal weights and corticosterone-binding globulin levels). These results emphasize the importance of the serotonergic innervation in maintaining hippocampal corticosteroid receptor gene expression. It is suggested that 5-hydroxytryptamine1C receptors may be involved in mediating the effects of serotonin on hippocampal glucocorticoid receptor and mineralocorticoid receptor expression and perhaps mood.