title: The role of GABAergic signalling in stress-induced suppression of gonadotrophin-releasing hormone pulse generator frequency in female rats.
abstract: Stress exerts profound inhibitory effects on reproductive function by suppressing the pulsatile release of gonadotrophin-releasing hormone (GnRH) and therefore luteinising hormone (LH). This effect is mediated in part via the corticotrophin-releasing factor (CRF) system, although another potential mechanism is via GABAergic signalling within the medial preoptic area (mPOA) because this has known inhibitory influences on the GnRH pulse generator and shows increased activity during stress. In the present study, we investigated the role of the preoptic endogenous GABAergic system in stress-induced suppression of the GnRH pulse generator. Ovariectomised oestradiol-replaced rats were implanted with bilateral and unilateral cannulae targeting toward the mPOA and lateral cerebral ventricle, respectively; blood samples (25 μl) were taken via chronically implanted cardiac catheters every 5 min for 6 h for the measurement of LH pulses. Intra-mPOA administration of the specific GABA(A) receptor antagonist, bicuculline (0.2 pmol each side, three times at 20-min intervals) markedly attenuated the inhibitory effect of lipopolysaccharide (LPS; 25 μg/kg i.v.) but not restraint (1 h) stress on pulsatile LH secretion. By contrast, restraint but not LPS stress-induced suppression of LH pulse frequency was reversed by application of the selective GABA(B) receptor antagonist, CGP-35348, into the mPOA (1.5 nmol each side, three times at 20-min intervals). However, intra-mPOA application of either bicuculline or CGP-35348 attenuated the inhibitory effect of CRF (1 nmol i.c.v.) on the pulsatile LH secretion. These data indicate a pivotal and differential role of endogenous GABAergic signalling in the mPOA with respect to mediating psychological and immunological stress-induced suppression of the GnRH pulse generator.
authors.affiliation: Division of Women's Health, School of Medicine, King's College London, Guy's Campus, London, UK.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lin
authors.forename: X F
authors.initials: XF
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Shao
authors.forename: M H
authors.initials: MH
authors.lastname: Hu
authors.forename: A L R
authors.initials: AL
authors.lastname: Goundry
authors.forename: A
authors.initials: A
authors.lastname: Jeyaram
authors.forename: S L
authors.initials: SL
authors.lastname: Lightman
authors.forename: K T
authors.initials: KT
authors.lastname: O'Byrne
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010052:Ovariectomy; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013312:Stress, Physiological; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D007987:Gonadotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; D007986:Luteinizing Hormone; D001640:Bicuculline