title: Serotonin acts through 5-HT1 and 5-HT2 receptors to exert biphasic actions on GnRH neuron excitability in the mouse.
abstract: The effect of serotonin (5-HT) on the electrical excitability of GnRH neurons was examined using gramicidin perforated-patch electrophysiology in transgenic GnRH-green fluorescent protein mice. In diestrous female, the predominant effect of 5-HT was inhibition (70%) with 50% of these cells also exhibiting a late-onset excitation. Responses were dose dependent (EC(50) = 1.2μM) and persisted in the presence of amino acid receptor antagonists and tetrodotoxin, indicating a predominant postsynaptic action of 5-HT. Studies in neonatal, juvenile, peripubertal, and adult mice revealed that 5-HT exerted less potent responses from GnRH neurons with advancing postnatal age in both sexes. In adult male mice, 5-HT exerted less potent hyperpolarizing responses with more excitations compared with females. In addition, adult proestrous female GnRH neurons exhibited reduced inhibition and a complete absence of biphasic hyperpolarization-excitation responses. Studies using 5-HT receptor antagonists demonstrated that the activation of 5-HT(1A) receptors mediated the inhibitory responses, whereas the excitation was mediated by the activation of 5-HT(2A) receptors. The 5-HT-mediated hyperpolarization involved both potassium channels and adenylate cyclase activation, whereas the 5-HT excitation was dependent on protein kinase C. The effects of exogenous 5-HT were replicated using fluoxetine, which enhances endogenous 5-HT levels. These studies demonstrate that 5-HT exerts a biphasic action on most GnRH neurons whereby a fast 5HT(1A)-mediated inhibition occurs alongside a slow 5-HT(2A) excitation. The balance of 5-HT-evoked inhibition vs excitation is developmentally regulated, sexually differentiated, and variable across the estrous cycle and may play a role in regulation of hypothalamic-pituitary-gonadal axis throughout postnatal development.
authors.affiliation: Department of Oral Physiology (J.P.B., S.K.H.), School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeonju 561-756, Republic of Korea; and Centre for Neuroendocrinology and Department of Physiology (J.R., A.E.H.), University of Otago School of Medical Sciences, Dunedin 9054, New Zealand.
authors.forename: Janardhan P
authors.initials: JP
authors.lastname: Bhattarai
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.forename: Allan E
authors.initials: AE
authors.lastname: Herbison
authors.forename: Seong Kyu
authors.initials: SK
authors.lastname: Han
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*
chemical_list: D044263:Receptors, Serotonin, 5-HT1; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; D007987:Gonadotropin-Releasing Hormone