Acute and long-term treatments with the selective serotonin reuptake inhibitor citalopram modulate the HPA axis activity at different levels in male rats

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