CHRONIC TREATMENT OF RATS WITH THE ANTIDEPRESSANT AMITRIPTYLINE ATTENUATES THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM

The effects of the tricyclic antidepressant amitriptyline on the rat h ypothalamic-pituitary-adrenocortical (HPA) system were studied. The ti me-course experiments showed that amitriptyline, given via the drinkin g water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippoca mpal mineralocorticoid receptor (MR) levels were down-regulated at day s 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 ( +74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid rec eptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 ( -17%), transiently up-regulated by 26% at 5 weeks, and indistinguishab le from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrati ons were elevated and neocortical receptor levels were not altered. Do se-response experiments showed significant decreases in adrenal weight when rats were treated with 4.5 (-14%), 8.8 (-16%) and 14.5 (-13%) mg /kg.day antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/kg.day doses when the ratio of adrenal weight to body w eight was considered. The dose-response relationship regarding hippoca mpal GR content displayed an inverted U-shaped curve, whereas this was less marked for MR levels. A dose of 4.5 mg/kg.day appeared to be opt imal for the rise in MR as well as GR. Concerning the neuroendocrine i mplications of chronic antidepressant treatment, amitriptyline (5 week s, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-in duced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous ex periments have forwarded a role of limbic MR in the tonic control of b asal HPA activity. Based on the present data, we hypothesize that duri ng amitriptyline treatment a rise in limbic MR may be the initial phen omenon in a successively adjusting HPA system, as evidenced by the dec reasing plasma hormone concentrations, declining adrenal size, and up- regulation of GR in particular brain regions.