Gonadal steroid modulation of stress-induced hypothalamo-pituitary-adrenal activity and anxiety behavior: role of central oxytocin

Endocrinology. 2006 May;147(5):2423-31. doi: 10.1210/en.2005-1079. Epub 2006 Jan 26.


Intracerebroventricular administration of oxytocin reduces anxiety behavior and hypothalamo-pituitary-adrenal (HPA) responses to stress in female rats. Similar changes are seen in late-pregnant rats, and oxytocin-sensitive pathways may mediate these effects. This study investigated anxiety behavior and stress responses using a gonadal steroid model of late pregnancy, which is known to increase endogenous oxytocin expression. Compared with continuous progesterone treatment, 3-d withdrawal of progesterone after 11-d treatment of ovariectomized rats with estradiol and progesterone resulted in increased binding of the oxytocin receptor ligand [(125)I]d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]ornithine vasotocin in selective forebrain regions, including the ventrolateral septum and ventromedial hypothalamus. Behavior in the elevated plus-maze indicated that progesterone withdrawal had an anxiolytic effect, and this was associated with lower levels of c-fos mRNA expression in the ventral hippocampus, an area previously shown to be sensitive to oxytocin. In other groups of animals, the plasma corticosterone response to a psychological stress (10 min of 114 dB white noise) was significantly attenuated by this steroid manipulation. Furthermore, simultaneous infusion of the selective oxytocin receptor antagonist desGlyNH(2), d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT during the period of progesterone withdrawal reversed this attenuation of noise-induced HPA activation, indicating a role for endogenous oxytocin in this effect. Thus, mimicking the steroid profile of late pregnancy leads to a reduction in anxiety behavior and attenuates HPA activity induced by mild stress. These effects appear to be mediated through the involvement of central oxytocin neurotransmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / pathology*
  • Animals
  • Anxiety
  • Female
  • Humans
  • Hypothalamus / metabolism
  • Hypothalamus / pathology*
  • Ligands
  • Neurotransmitter Agents
  • Oxytocin / metabolism*
  • Pituitary Gland / pathology*
  • Pregnancy
  • Pregnancy, Animal
  • Progesterone / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Oxytocin / metabolism
  • Steroids / metabolism*
  • Time Factors


  • Ligands
  • Neurotransmitter Agents
  • RNA, Messenger
  • Receptors, Oxytocin
  • Steroids
  • Progesterone
  • Oxytocin