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Gonadal Steroid Modulation of Stress-Induced Hypothalamo-Pituitary-Adrenal Activity and Anxiety Behavior: Role of Central Oxytocin

Human and Clinical Sciences Research Center, University of Nottingham, Queen’s Medical Center (R.J.W.), Nottingham NG7 2UH, United Kingdom; University Research Center for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary (L.E.G., Y.M.K., S.A.W., S.L.L.), Bristol BS2 8HW, United Kingdom; and Psychobiology Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle Medical School (C.D.I.), Newcastle NE2 4HH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Richard Windle, Faculty of Medicine and Health Sciences, University of Nottingham School of Nursing, Queen’s Medical Center, Room B59b, Nottingham NG7 2UH, United Kingdom. E-mail: richard.windle{at}nottingham.ac.uk.

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 [¹²⁵I]d(CH₂)₅[Tyr(Me)²,Thr⁴,Tyr-NH₂⁹]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 desGlyNH₂, d(CH₂)₅[Tyr(Me)²,Thr⁴]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.