title: Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.
abstract: Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.
authors.affiliation: Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wenhua 1st Road, Guishan Dist., Taoyuan 333, Taiwan.
authors.forename: Ya-Tin
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wenhua 1st Road, Guishan Dist., Taoyuan 333, Taiwan.
authors.forename: Tzu-Yu
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wenhua 1st Road, Guishan Dist., Taoyuan 333, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Yu-Lian
authors.initials: YL
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Chang Gung Memorial Hospital, No. 5, Fusing St., Guichan Dist., Taoyuan 333, Taiwan.
authors.forename: Yuan-Ji
authors.initials: YJ
authors.lastname: Day
authors.affiliation: Department of Chemistry, Fu Jen Catholic University, No. 510, Zhongzheng Road, Xinzhuang Dist., New Taipei City 242, Taiwan.
authors.forename: Che-Chien
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Guo-Jen
authors.initials: GJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wenhua 1st Road, Guishan Dist., Taoyuan 333, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Electronic address: jinchen@mail.cgu.edu.tw.
authors.forename: Jin-Chung
authors.initials: JC
authors.lastname: Chen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001007:Anxiety; D001008:Anxiety Disorders / Q000378:metabolism; D002908:Chronic Disease / Q000523:psychology; D003345:Corticosterone / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003863:Depression / Q000503:physiopathology*; D003866:Depressive Disorder / Q000503:physiopathology; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism* / Q000502:physiology; D013312:Stress, Physiological / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D011965:Receptors, Glucocorticoid; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone
keywords: Depression; Hypothalamic-pituitary-adrenal axis (HPA axis); NPFFR2; Neuropeptide FF (NPFF); Paraventricular nucleus (PVN); Stress