Abnormal interactions between serotonin (5-hydroxytryptamine) and glucocorticoids, notably in the hippocampus, may underpin neuroendocrine, affective and cognitive dysfunction in depression and ageing. Glucocorticoids act via intracellular glucocorticoid and mineralocorticoid receptors, whereas 5-hydroxytryptamine binds to a family of transmembrane sites; both cross- and auto-regulation have been proposed. To determine the roles of 5-hydroxytryptamine and corticosterone in the short-term control of hippocampal receptor gene expression, we used 3,4-methylenedioxymethamphetamine (20 mg/kg), which causes acute release of both 5-hydroxytryptamine and corticosterone. 3,4-methylenedioxymethamphetamine increased mineralocorticoid receptor messenger RNA expression throughout the hippocampus after 16 h. In rats with fixed glucocorticoid levels (adrenalectomy plus corticosterone pellets) this effect was lost in CA1-4, suggesting corticosterone-mediation, but maintained in the dentate gyrus, indicating 5-hydroxytryptamine involvement. In contrast, 3,4-methylenedioxymethamphetamine decreased glucocorticoid receptor messenger RNA expression in the dentate gyrus and CA1 within 4 h, but only in adrenal-intact rats, suggesting corticosterone control. 5-Hydroxytryptamine1A receptor messenger RNA expression was decreased in CA1 in both groups of rats, but increased in the dentate gyrus only in corticosterone-fixed rats, suggesting 5-hydroxytryptamine differentially regulates expression of this gene within hippocampal subfields. 5-hydroxytryptamine2C receptor messenger RNA was decreased in ventral CA1 only in adrenal-intact rats, suggesting a corticosterone effect, and decreased in the subiculum in both groups, indicating 5-hydroxytryptamine mediation. These results show the complexity and intricate subregional-specificity of 5-hydroxytryptamine and corticosterone interactions upon hippocampal corticosteroid and 5-hydroxytryptamine receptor gene expression. 3,4-Methylenedioxymethamphetamine-induced alterations in hippocampal receptor gene expression may play a role in the mood and behavioural changes associated with this drug of abuse.