Hypothalamic-pituitary-adrenocortical axis changes in the rat after long-term treatment with the reversible monoamine oxidase-A inhibitor moclobemide

J M Reul, M S Labeur, D E Grigoriadis, E B De Souza, F Holsboer

Research output: Contribution to journalArticle (Academic Journal)

176 Citations (Scopus)

Abstract

The effects of the reversible monoamine oxidaseA (MAOA) inhibitor moclobemide on the rat hypothalamic-pituitary-adrenocortical (HPA) axis were studied. The time-course experiments showed that moclobemide, given via the drinking water (4.5 mg/kg/day), produces significant decreases (p < 0.05) in adrenal weight after 5 (-23%) and 7 weeks (-16%) of treatment. It was found that long-term moclobemide treatment had neuroanatomically distinct effects on corticosteroid receptor expression. Hippocampal mineralocorticoid receptor (MR) levels were upregulated at 2 (+65%), 5 (+76%) and 7 (+19%) weeks of treatment. Glucocorticoid receptor (GR) levels in this limbic brain structure were slightly up-regulated by 10% at 5 weeks, and indistinguishable from controls after 2 and 7 weeks of treatment. After 5 weeks of treatment, MR levels were unchanged in the hypothalamus, and increased by 44, 24 and 28% in the neocortex, amygdala and anterior pituitary, respectively. GR concentrations were elevated by 24 and 14% in the hypothalamus and anterior pituitary, respectively, whereas neocortical and amygdaloid receptor levels were not altered. After 5 weeks of moclobemide treatment, marked decreases in [125I]Tyr0-ovine corticotropin-releasing hormone ([125I])-oCRH binding capacity and proopiomelanocortin (POMC) mRNA content were observed in the anterior pituitary. Regarding the functional implications of long-term anti-depressant treatment, moclobemide treatment (5 weeks, 4.5 mg/kg/day) significantly attenuated stress (30-min novel environment)-induced plasma ACTH (-35%) and corticosterone (-29%) levels; no changes were observed in basal plasma ACTH and corticosterone levels. In conclusion, this study shows that moclobemide has a concerted influence on multiple elements of the HPA axis manifesting functionally as a reduced neuroendocrine responsiveness to stress. In previous experiments, it was found that the structurally and pharmacologically distinct antidepressant amitriptyline after long-term administration also attenuated HPA axis activity. We postulate that an adjustement of HPA axis activity may be regarded as a common denominator for clinically efficacious antidepressant drugs.

Original languageEnglish
Pages (from-to)509-19
Number of pages11
JournalNeuroendocrinology
Volume60
Issue number5
Publication statusPublished - Nov 1994

Keywords

  • Adrenal Cortex
  • Animals
  • Benzamides
  • Brain
  • Gene Expression
  • Hypothalamus
  • Kinetics
  • Male
  • Moclobemide
  • Monoamine Oxidase Inhibitors
  • Organ Size
  • Pituitary Gland
  • Pituitary Gland, Anterior
  • Pro-Opiomelanocortin
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Steroid

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