EFFECT OF CHRONIC TREATMENT WITH THE ANTIDEPRESSANT TIANEPTINE ON THEHYPOTHALAMO-PITUITARY-ADRENAL AXIS

The effects of acute and chronic administration of tianeptine, a novel antidepressant agent, on the hypothalamo-pituitary adrenal axis were studied in the adult male rat. A single injection of tianeptine did no t alter the activity of the hypothalamo-pituitary-adrenal axis. In con trast, chronic administration of tianeptine (10 mg/kg twice a day for 15 days) induced a significant decrease in the concentration of cortic otropin-releasing factor (CRF) in the hypothalamus and adrenocorticotr opin (ACTH) in the anterior lobe of the pituitary. Chronic tianeptine treatment did not modify CRF levels in the cerebral cortex and hippoca mpus, and did not alter alpha-melanocyte-stimulating hormone and beta- endorphin levels in the neurointermediate lobe of the pituitary. Using the in situ hybridization technique, we observed that chronic adminis tration of tianeptine did not modify CRF mRNA levels in the paraventri cular nucleus of the hypothalamus. The effect of chronic tianeptine tr eatment on the neuroendocrine response to stress was also investigated . Tube restraint stress for 30 min induced a significant depletion of hypothalamic CRF and a substantial increase of plasma ACTH and cortico sterone. Tianeptine abolished the stress-induced reduction of hypothal amic CRF concentration and markedly reduced the stress-induced increas e in plasma ACTH and corticosterone levels. Taken together, these resu lts suggest that tianeptine acts primarily at the level of the hypotha lamus: (1) in unstressed rats, tianeptine reduces hypothalamic CRF and pituitary ACTH contents; (2) in stressed animals, tianeptine attenuat es the activation of the hypothalamo-pituitary-adrenal axis.