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This version published online on October 14, 2004
Endocrinology, doi:10.1210/en.2004-1053
A more recent version of this article appeared on January 1, 2005
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Submitted on August 11, 2004
Accepted on October 5, 2004

The role of the locus coeruleus in corticotropin-releasing hormone and stress-induced suppression of pulsatile luteinizing hormone secretion in the female rat

J. C. Mitchell, X. F. Li, L. Breen, J-C. Thalabard, and K. T. O'Byrne*

Division of Reproductive Health, Endocrinology and Development, School of Medicine, New Hunt's House, King's College London, Guy's Campus, SE1 1UL, UK; Biostatistiques-Medecine de la Reproduction, Hopital Necker, 149, rue de Sevres, 75743 Paris Cedex 15, France

* To whom correspondence should be addressed. E-mail: Kevin.o'byrne{at}kcl.ac.uk.

Despite a wealth of evidence for CRH (CRH) mediating stress-induced suppression of the hypothalamic gonadotropin-releasing hormone (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 (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 17{beta}-estradiol (E2) or oil filled subcutaneous capsules, were implanted with bilateral LC and iv cannulae. Central administration of CRH (10 ng - 1 µg) resulted in a dose-dependent suppression of LH pulses, which was reversed by a CRH receptor antagonist ({alpha}-helical CRF9-41, 1 µg). The induction of c-Fos expression in glutamic acid decarboxylase (GAD67) immunostained neurons in the preoptic area, suggests GABAergic activation in response to intracoerulear administration of CRH; E2 further increased the percentage of GAD67 positive neurons that expressed Fos and augmented suppression of LH pulses. Furthermore, intracoerulear administration of {alpha}-helical CRF9-41 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.
Key words: CRH • LH pulses • locus coeruleus • stress • rat




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