Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system

J M Reul, I Stec, M Söder, F Holsboer

Research output: Contribution to journalArticle (Academic Journal)peer-review

343 Citations (Scopus)


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/, 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/ antidepressant, but this applied only for the 4.5- (-14%) and 8.8- (-12%) mg/ 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/ 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/ 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.

Original languageEnglish
Pages (from-to)312-20
Number of pages9
Issue number1
Publication statusPublished - Jul 1993


  • Adrenal Cortex
  • Adrenal Glands
  • Adrenocorticotropic Hormone
  • Amitriptyline
  • Animals
  • Corticosterone
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Hippocampus
  • Hypothalamus
  • Kinetics
  • Male
  • Organ Size
  • Pituitary Gland
  • Rats
  • Rats, Wistar
  • Receptors, Glucocorticoid
  • Receptors, Mineralocorticoid
  • Receptors, Steroid
  • Up-Regulation


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