title: Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice.
abstract: Anxiety disorders are among the most prevalent neuropsychiatric conditions, but their precise aetiology and underlying pathophysiological processes remain poorly understood. In light of putative anatomical and functional interactions of the relaxin-3/RXFP3 system with anxiety-related neural circuits, we assessed the ability of central administration of the RXFP3 agonist, RXFP3-A2, to alter anxiety-like behaviours in adult C57BL/6J mice. We assessed how RXFP3-A2 altered performance in tests measuring rodent anxiety-like behaviour (large open field (LOF), elevated plus maze (EPM), light/dark (L/D) box, social interaction). We examined effects of RXFP3-A2 on low 'basal' anxiety, and on elevated anxiety induced by the anxiogenic benzodiazepine, FG-7142; and explored endogenous relaxin-3/RXFP3 signalling modulation by testing effects of an RXFP3 antagonist, R3(B1-22)R, on these behaviours. Intracerebroventricular (icv) injection of RXFP3-A2 (1 nmol, 15 min pre-test) did not alter anxiety-like behaviour under 'basal' conditions in the LOF, EPM or L/D box, but reduced elevated indices of FG-7142-induced (30 mg/kg, ip) anxiety-like behaviour in the L/D box and a single-chamber social interaction test. Furthermore, R3(B1-22)R (4 nmol, icv, 15 min pre-test) increased anxiety-like behaviour in the EPM (reflected by reduced entries into the open arms), but not consistently in the LOF, L/D box or social interaction tests, suggesting endogenous signaling only weakly participates in regulating 'basal' anxiety-like behaviour, in line with previous studies of relaxin-3 and RXFP3 gene knockout mice. Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Cary
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia.
authors.forename: Berenice E
authors.initials: BE
authors.lastname: Chua
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia.
authors.forename: Annie
authors.initials: A
authors.lastname: Yang
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Fazel
authors.initials: F
authors.lastname: Shabanpoor
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; School of Chemistry, The University of Melbourne, Victoria, Australia.
authors.forename: Mohammad Akhter
authors.initials: MA
authors.lastname: Hossain
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; School of Chemistry, The University of Melbourne, Victoria, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.affiliation: School of Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: K Johan
authors.initials: KJ
authors.lastname: Rosengren
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia. Electronic address: andrew.gundlach@florey.edu.au.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012065:Relaxin / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D002243:Carbolines; D043562:Receptors, G-Protein-Coupled; C505050:SALPR protein, mouse; C512898:relaxin-3 protein, mouse; C035874:FG 7142; D012065:Relaxin
keywords: Anxiety; Arousal; FG-7142; Neuropeptide receptor; RXFP3; Relaxin-3; Stress