Both central serotonergic dysfunction and glucocorticoid hypersecretion have been separately implicated in the aetiology of affective disorders. The hippocampus highly expresses receptors for 5-hydroxytryptamine and glucocorticoids, and adrenalectomy alters the responsivity of hippocampal neurons to 5-hydroxytryptamine. The hippocampus thus represents a prime locus for interactions between the two systems. In this study we examined the effects of glucocorticoid manipulations on neuronal expression of messenger RNA encoding corticosteroid receptor and 5-hydroxytryptamine receptor subtypes in the hippocampus and 5-hydroxytryptamine1A messenger RNA expression in the dorsal raphe, in the rat. Interestingly, there was no effect of adrenalectomy on 5-hydroxytryptamine1A or 5-hydroxytryptamine2A receptor messenger RNA expression in the dorsal or ventral hippocampus at any time point measured. Furthermore, no changes in 5-hydroxytryptamine1A receptor gene expression were seen in the dorsal raphe (encoding autoreceptors) after adrenalectomy. However, 5-hydroxytryptamine2C (5-hydroxytryptamine1C) receptor messenger RNA expression was increased specifically in posterior CA1 and CA3 neurons following adrenalectomy, an effect that was reversed by glucocorticoid replacement. Following adrenalectomy, glucocorticoid and mineralocorticoid receptor messenger RNA expression increased in the dentate gyrus, CA1 and CA3 subfields of the hippocampus. These increases were apparent 6 h after adrenalectomy, were maintained at two days, but 14 days after adrenalectomy hippocampal glucocorticoid receptor and mineralocorticoid receptor gene expression had returned to control levels. These effects of adrenalectomy were abolished by dexamethasone, but not aldosterone administration, suggesting mediation by autoregulatory glucocorticoid receptors. Our results show that adrenalectomy only transiently increases corticosteroid receptor gene expression in the hippocampus, and selectively increases hippocampal 5-hydroxytryptamine2C receptor messenger RNA expression. The resulting change in 5-hydroxytryptamine2C receptor-mediated responses may produce the alterations in hippocampal neuronal activity in response to 5-hydroxytryptamine observed after adrenalectomy.