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Central Orexin A Has Site-Specific Effects on Luteinizing Hormone Release in Female Rats

Departments of Obstetrics and Gynecology/Physiology (J.F.M., A.S., H.Y., V.S., C.A.W.), St. George’s Hospital Medical School, London SW17 0RE, United Kingdom; Department of Metabolic Medicine (C.J.S., A.R.K., S.R.B.), Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom; and Center for Neuroscience Research (M.-L.G., S.E.G., T.K., C.W.C.), King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom

Address all correspondence and requests for reprints to: Prof. C. A. Wilson, Department of Obstetrics and Gynecology/Physiology, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail: cwilson{at}sghms.ac.uk.

Orexin A stimulates GnRH release from hypothalamic explants in vitro. The sites of action of orexin A in the regulation of LH release have been investigated in vivo in ovariectomized rats that were given vehicle or estradiol benzoate (EB), with or without an injection of progesterone 48 h later. Orexin A was administered intrahypothalamically under Saffan anesthesia, 50 h after the EB or vehicle; its effects on plasma LH levels were monitored in sequential blood samples. Orexin A (1.0 µg/side) injected into the rostral preoptic area (rPOA) at the level of the organum vasculosum of the lamina terminalis had a stimulatory effect on LH release in EB-treated ovariectomized rats. When orexin A was injected into the medial POA (mPOA) or the arcuate/median eminence, it had an inhibitory effect on the LH surge that occurs in ovariectomized rats primed with EB plus progesterone. Orexin A injected into the mPOA also reduced LH levels in ovariectomized rats untreated with ovarian steroids. Both the stimulatory and inhibitory effects of orexin A were antagonized by SB334867A, a selective orexin 1 receptor antagonist. Furthermore, when given alone into the rPOA, this antagonist attenuated the LH surge induced by EB plus progesterone. Thus, orexin appears to have a dual effect on LH release, being stimulatory in the rPOA and inhibitory in the mPOA or arcuate/median eminence. Both effects may be mediated, at least in part, by the orexin 1 receptor. Double label immunohistochemistry revealed close appositions between orexin A immunoreactive varicosities and a small proportion of GnRH cell bodies in the rPOA. It is suggested that the stimulatory effect of orexin A on LH release may involve direct actions on GnRH neurons.

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