It is well established that the maximal therapeutic effect of selective serotonin reuptake inhibitors (SSRI) are achieved in depressive patients after several weeks of treatment, but the adaptive processes leading to the therapeutic effects are unclear. It has been shown that hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis in depressive patients is affected by long-term antidepressant treatment. These changes occur in association with the mood normalising effect, suggesting that antidepressants affect the HPA axis and this effect is associated with the therapeutic effect. Male Wistar rats were treated with the SSRI, citalopram, to investigate time-related changes in components that may be involved in the desensitization of the HPA axis. A single injection of citalopram (10 mg/kg, s.c.), increased the plasma levels of ACTH and corticosterone in a dose-dependent manner and increased the number of c-Fos containing cells in the hypothalamic paraventricular nucleus. A daily treatment with the same compound (10 mg/kg, s.c.) for 14 days decreased the expression of POMC mRNA ( approximately 40%). In addition, a blunted response to citalopram was observed in animals long-term treated with citalopram. Also CRF-stimulated cAMP accumulation in the pituitary was altered. In conclusion, acute citalopram activated the HPA-axis at the hypothalamic level and long-term citalopram treatment desensitized the HPA-axis at the pituitary level. These results support the hypothesis that the therapeutic effects of long-term antidepressant treatments reduce HPA axis responsiveness.