Neuroendocrine profile in a rat model of psychosocial stress: relation to oxidative stress

Antioxid Redox Signal. 2013 Apr 20;18(12):1385-99. doi: 10.1089/ars.2012.4569.


Aims: Psychosocial stress alters the hypothalamic-pituitary-adrenal axis (HPA-axis). Increasing evidence shows a link between these alterations and oxidant elevation. Oxidative stress is implicated in the stress response and in the pathogenesis of neurologic and psychiatric diseases. NADPH oxidases (NOXs) are a major source of reactive oxygen species (ROS) in the central nervous system. Here, we investigated the contributory role of NOX2-derived ROS to the development of neuroendocrine alterations in a rat model of chronic psychosocial stress, the social isolation.

Results: Significant elevations in the hypothalamic levels of corticotropin-releasing factor and plasmatic adrenocorticotropic hormone were observed from 4 weeks of social isolation. Increased levels of peripheral markers of the HPA-axis (plasmatic and salivary corticosterone) were observed at a later time point of social isolation (7 weeks). Alteration in the exploratory activity of isolated rats followed the same time course. Increased expression of markers of oxidative stress (8-hydroxy-2-deoxyguanosine [8OhdG] and nitrotyrosine) and NOX2 mRNA was early detectable in the hypothalamus of isolated rats (after 2 weeks), but later (after 7 weeks) in the adrenal gland. A 3-week treatment with the antioxidant/NOX inhibitor apocynin stopped the progression of isolation-induced alterations of the HPA-axis. Rats with a loss-of-function mutation in the NOX2 subunit p47(phox) were totally protected from the alterations of the neuroendocrine profile, behavior, and increased NOX2 mRNA expression induced by social isolation.

Innovation: We demonstrate that psychosocial stress induces early elevation of NOX2-derived oxidative stress in the hypothalamus and consequent alterations of the HPA-axis, leading ultimately to an altered behavior.

Conclusion: Pharmacological targeting of NOX2 might be of crucial importance for the treatment of psychosocial stress-induced psychosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Acetophenones / pharmacology
  • Adrenal Glands / metabolism
  • Adrenocorticotropic Hormone / blood*
  • Animals
  • Antioxidants / pharmacology
  • Biomarkers / blood
  • Corticosterone / blood*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / metabolism
  • Female
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamus / metabolism
  • Male
  • Mutation
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Neurosecretory Systems / metabolism
  • Oxidative Stress*
  • Pituitary-Adrenal System / metabolism
  • Psychosocial Deprivation
  • Psychotic Disorders / metabolism
  • Rats
  • Rats, Wistar
  • Restraint, Physical
  • Saliva / metabolism
  • Social Isolation
  • Stress, Psychological / blood*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism


  • Acetophenones
  • Antioxidants
  • Biomarkers
  • 3-nitrotyrosine
  • Tyrosine
  • 8-Hydroxy-2'-Deoxyguanosine
  • Adrenocorticotropic Hormone
  • acetovanillone
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Deoxyguanosine
  • Corticosterone