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The Role of the Locus Coeruleus in Corticotropin-Releasing Hormone and Stress-Induced Suppression of Pulsatile Luteinizing Hormone Secretion in the Female Rat

Division of Reproductive Health (J.C.M., X.F.L., L.B., K.T.O.), Endocrinology and Development, School of Medicine, New Hunt’s House, King’s College London, London SE1 1UL, United Kingdom; and Biostatistiques-Medecine de la Reproduction (J.-C.T.), Hopital Necker, 75743 Paris Cedex 15, France

Address all correspondence and requests for reprints to: Dr. K. T. O’Byrne, Division of Reproductive Health, Endocrinology and Development, School of Medicine, 2.36D New Hunt’s House, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom. E-mail: Kevin.o'byrne{at}kcl.ac.uk.

Despite a wealth of evidence for CRH mediating stress-induced suppression of the hypothalamic GnRH pulse generator, and hence reproductive dysfunction, the site and mechanism of action remains elusive. The locus coeruleus (LC), a prominent noradrenergic brain stem nucleus, is innervated by CRH neurons, mediates several behavioral stress responses, and is implicated in the control of pulsatile LH secretion. The aim of this study was to test the hypothesis that LC CRH has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats with 17ß-estradiol or oil-filled sc capsules were implanted with bilateral LC and iv cannulae. Central administration of CRH (10 ng to 1 µg) resulted in a dose-dependent suppression of LH pulses, which was reversed by a CRH receptor antagonist (-helical CRF_9–41, 1 µg). The induction of c-fos expression in glutamic acid decarboxylase₆₇ immunostained neurons in the preoptic area suggests activation of the secretion of -aminobutyric acid in response to intracoerulear administration of CRH; 17ß-estradiol further increased the percentage of glutamic acid decarboxylase₆₇-positive neurons that expressed fos and augmented suppression of LH pulses. Furthermore, intracoerulear administration of -helical CRF_9–41 completely blocked restraint stress-induced suppression of LH pulses, without affecting the inhibitory response to hypoglycemia. These results suggest that CRH innervation of the LC may play a pivotal, but differential, role in the normal physiological response of stress-induced suppression of the GnRH pulse generator and hence the reproductive system.

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