Animal and clinical studies of gene-environment interactions have helped elucidate the mechanisms involved in the pathophysiology of several mental illnesses including anxiety, depression, and schizophrenia; and have led to the discovery of improved treatments. The study of neuropeptides and their receptors is a parallel frontier of neuropsychopharmacology research and has revealed the involvement of several peptide systems in mental illnesses and identified novel targets for their treatment. Relaxin-3 is a newly discovered neuropeptide that binds, and activates the G-protein coupled receptor, RXFP3. Existing anatomical and functional evidence suggests relaxin-3 is an arousal transmitter which is highly responsive to environmental stimuli, particularly neurogenic stressors, and in turn modulates behavioral responses to these stressors and alters key neural processes, including hippocampal theta rhythm and associated learning and memory. Here, we review published experimental data on relaxin-3/RXFP3 systems in rodents, and attempt to highlight aspects that are relevant and/or potentially translatable to the etiology and treatment of major depression and anxiety. Evidence pertinent to autism spectrum and metabolism/eating disorders, or related psychiatric conditions, is also discussed. We also nominate some key experimental studies required to better establish the therapeutic potential of this intriguing neuromodulatory signaling system, including an examination of the impact of RXFP3 agonists and antagonists on the overall activity of distinct or common neural substrates and circuitry that are identified as dysfunctional in these debilitating brain diseases.
Keywords: relaxin-3, RXFP3, neuropeptide, arousal, stress, mood and depression, autism spectrum disorders, eating disorders
Citation: Smith CM, Walker AW, Hosken IT, Chua BE, Zhang C, Haidar M and Gundlach AL (2014) Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases? Front. Pharmacol. 5:46. doi: 10.3389/fphar.2014.00046
Received: 28 October 2013; Accepted: 28 February 2014;
Published online: 21 March 2014.
Edited by:Laurence Lanfumey, Institut National de la Santé et de la Recherche Médicale, France
Reviewed by:Sara Morley-Fletcher, Centre National de la Recherche Scientifique-University Lille, France
Copyright © 2014 Smith, Walker, Hosken, Chua, Zhang, Haidar and Gundlach. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Craig M. Smith and Andrew L. Gundlach, Peptide Neurobiology Laboratory, Neuropeptides Division, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia e-mail: email@example.com; firstname.lastname@example.org