Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases?

Abstract

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.

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

“…The largest population of relaxin-3 expressing neurons is located within the tegmental area known as the nucleus incertus (NI), and these neurons project broadly throughout the brain [15][16][17][18][19]. The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25]. Anatomical and functional data [15][16][17][18] suggest that relaxin-3/RXFP3 systems may interact directly with monoamine [19,26] and other peptide systems [27][28][29], and/or act at shared downstream limbic and hypothalamic target areas to modulate 'anxiety' and other stress-related responses [30][31][32][33][34].…”

Synthesis and pharmacological characterization of a europium-labelled single-chain antagonist for binding studies of the relaxin-3 receptor RXFP3

“…d Pooled binding affinities, expressed as pKi values, for R3 and R3B1-22R which display no significant difference between agonist and antagonist binding. Data are presented as mean ± SEM of triplicates from at least three independent experiments and has therapeutic relevance for several disease states (Smith et al 2014). However, the development of RXFP3-selective ligands requires a robust and reliable receptor binding screening method.…”

Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro

“…Smaller nuclei of relaxin-3 neurons are also present in various areas throughout the brain, such as in the periaqueductal grey, pontine raphe and an area dorsal to the substantia nigra (Tanaka et al 2005;Ma et al 2007). Relaxin-3 has been implicated in several behaviours consistent with its proposed role as an arousal system (Smith et al 2014b;Ma et al 2016). For example, characterisation of relaxin-3 knockout (KO) and relaxin-3 receptor (RXFP3) KO mice revealed a hypoactive phenotype present during the dark phase (Smith et al 2012;Hosken et al 2015), and RXFP3 activation in rats is associated with an increase in food intake (Ganella et al 2012), suggesting involvement in motivated behaviours.…”