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 hypothalamic-pituitary-adrenocortical (HPA) system were studied. The time-course experiments showed that amitriptyline, given via the drinking water (4.5 mg/kg.day), produces significant decreases (P < 0.05) in adrenal weight after 5 (-20%) and 7 weeks (-21%) of treatment. Hippocampal mineralocorticoid receptor (MR) levels were down-regulated at days 3 (-27%) and 7 (-20%), and transiently up-regulated at 2 (+40%), 5 (+74%), and 7 (+18%) weeks of treatment. Hippocampal glucocorticoid receptor (GR) levels were slightly down-regulated at days 3 (-8%) and 7 (-17%), transiently up-regulated by 26% at 5 weeks, and indistinguishable from controls after 7 weeks of treatment. MR levels were unchanged in the hypothalamus and neocortex, whereas hypothalamic GR concentrations were elevated and neocortical receptor levels were not altered. Dose-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 weight was considered. The dose-response relationship regarding hippocampal 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 optimal for the rise in MR as well as GR. Concerning the neuroendocrine implications of chronic antidepressant treatment, amitriptyline (5 weeks, 4.5 mg/kg.day) produced significant decreases in basal (ACTH, -47%; corticosterone, -31%) as well as stress (30 min novel environment)-induced plasma ACTH (-38%) and corticosterone (-57%) levels. Previous experiments have forwarded a role of limbic MR in the tonic control of basal HPA activity. Based on the present data, we hypothesize that during amitriptyline treatment a rise in limbic MR may be the initial phenomenon in a successively adjusting HPA system, as evidenced by the decreasing plasma hormone concentrations, declining adrenal size, and up-regulation of GR in particular brain regions.
Max Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
J M
JM
Reul
I
I
Stec
M
M
Söder
F
F
Holsboer
D000302:Adrenal Cortex / Q000187:drug effects* / Q000502:physiology; D000311:Adrenal Glands / Q000033:anatomy & histology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000639:Amitriptyline / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011987:Receptors, Steroid; D000639:Amitriptyline; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone