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TitleAnxiogenic and stressor effects of the hypothalamic neuropeptide RFRP-3 are overcome by the NPFFR antagonist GJ14
Publication TypeJournal Article
Year of Publication2015
AuthorsKim, J.S., Brownjohn P.W., Dyer B.S., Beltramo M., Walker C.S., Hay D.L., Painter G.F., Tyndall J.D.A., and Anderson G.M.
Pagination4152 - 4162
Date Published2015
ISSN00137227 (ISSN)
KeywordsAnimal, animal behavior, animal cell, Animals, antagonists and inhibitors, anxiety, anxiolytic agent, article, Behavior, Animal, binding affinity, Blood, chemically induced, CHO cell line, CHO Cells, controlled study, corticosterone, corticosterone release, Cricetulus, drug effects, drug therapy, Female, G protein coupled receptor 54, gj 14, human, human cell, hypophysis adrenal system, Hypothalamo-Hypophyseal System, hypothalamus hypophysis adrenal system, hypothalamus hypophysis system, ligand binding, Male, mental stress, metabolism, Mice, mouse, nerve cell, neuropeptide, neuropeptide FF receptor, neuropeptide receptor, Neuropeptides, nonhuman, open field test, physiology, Pituitary-Adrenal System, priority journal, protein expression, Receptors, Neuropeptide, RFamide peptide, RFamide related peptide 3, stress, Stress, Psychological, tranquilizing activity, unclassified drug
AbstractRFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-Adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic andHPAaxis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety.Wealso show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders. © 2015 by the Endocrine Society.

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