Systemic N-terminal fragments of adrenocorticotropin reduce inflammation- and stress-induced anhedonia in rats

Psychoneuroendocrinology. 2017 Aug:82:173-186. doi: 10.1016/j.psyneuen.2017.04.019. Epub 2017 May 7.

Abstract

Emerging evidence implicates impaired self-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammation as important and closely related components of the pathophysiology of major depression. Antidepressants show anti-inflammatory effects and are suggested to enhance glucocorticoid feedback inhibition of the HPA axis. HPA axis activity is also negatively self-regulated by the adrenocorticotropic hormone (ACTH), a potent anti-inflammatory peptide activating five subtypes of melanocortin receptors (MCRs). There are indications that ACTH-mediated feedback can be activated by noncorticotropic N-terminal ACTH fragments such as a potent anti-inflammatory MC1/3/4/5R agonist α-melanocyte-stimulating hormone (α-MSH), corresponding to ACTH(1-13), and a MC3/5R agonist ACTH(4-10). We investigated whether intraperitoneal administration of rats with these peptides affects anhedonia, which is a core symptom of depression. Inflammation-related anhedonia was induced by a single intraperitoneal administration of a low dose (0.025mg/kg) of lipopolysaccharide (LPS). Stress-related anhedonia was induced by the chronic unpredictable stress (CUS) procedure. The sucrose preference test was used to detect anhedonia. We found that ACTH(4-10) pretreatment decreased LPS-induced increase in serum corticosterone and tumor necrosis factor (TNF)-α, and a MC3/4R antagonist SHU9119 blocked this effect. Both α-MSH and ACTH(4-10) alleviated LPS-induced anhedonia. In the CUS model, these peptides reduced anhedonia and normalized body weight gain. The data indicate that systemic α-MSH and ACTH(4-10) produce an antidepressant-like effect on anhedonia induced by stress or inflammation, the stimuli that trigger the release of ACTH and α-MSH into the bloodstream. The results suggest a counterbalancing role of circulating melanocortins in depression and point to a new approach for antidepressant treatment.

Keywords: ACTH; Anhedonia; Chronic unpredictable stress; Depression; LPS; Melanocortins.

MeSH terms

  • Adrenocorticotropic Hormone / metabolism
  • Adrenocorticotropic Hormone / pharmacology*
  • Anhedonia / drug effects*
  • Anhedonia / physiology
  • Animals
  • Corticosterone / blood
  • Depressive Disorder, Major / immunology
  • Depressive Disorder, Major / metabolism
  • Hypothalamo-Hypophyseal System / metabolism
  • Inflammation / immunology
  • Male
  • Peptide Fragments / pharmacology
  • Peptides / therapeutic use
  • Pituitary-Adrenal System / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin / metabolism
  • Receptors, Melanocortin / blood
  • Receptors, Melanocortin / metabolism
  • Stress, Psychological / metabolism
  • alpha-MSH / metabolism
  • alpha-MSH / pharmacology

Substances

  • Peptide Fragments
  • Peptides
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • alpha-MSH
  • Adrenocorticotropic Hormone
  • ACTH (4-10)
  • Corticosterone