Involvement of central relaxin-3 signalling in sodium (salt) appetite.

What is the central question of this study? Sodium appetite is controlled by conserved neuronal transmitter-receptor systems. Here, we tested the contribution made by relaxin family peptide 3 receptor (RXFP3), the cognate G-protein-coupled receptor for the neuropeptide relaxin-3. What is the main finding and its importance? Intracerebroventricular infusion of an RXFP3 antagonist reduced in a dose-dependent manner the volume of 0.

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

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).

Sensitivity to Chronic Methamphetamine Administration and Withdrawal in Mice with Relaxin-3/RXFP3 Deficiency.

Methamphetamine (METH) is a highly addictive psychostimulant, and cessation of use is associated with reduced monoamine signalling, and increased anxiety/depressive states. Neurons expressing the neuropeptide, relaxin-3 (RLN3), and its cognate receptor, RXFP3, constitute a putative 'ascending arousal system', which shares neuroanatomical and functional similarities with serotonin (5-HT)/dorsal raphe and noradrenaline (NA)/locus coeruleus monoamine systems. In light of possible synergistic roles of RLN3 and 5-HT/NA, endogenous RLN3/RXFP3 signalling may compensate for the temporary reduction in monoamine signalling associated with chronic METH withdrawal, which could alter the profile of 'behavioural despair', bodyweight reductions, and increases in anhedonia and anxiety-like behaviours observed following chronic METH administration.

Relaxin-3 receptor (RXFP3) signalling mediates stress-related alcohol preference in mice.

Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption.

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

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.

Central injection of relaxin-3 receptor (RXFP3) antagonist peptides reduces motivated food seeking and consumption in C57BL/6J mice.

Behavioural arousal in mammals is regulated by various interacting central monoamine- and peptide-neurotransmitter/receptor systems, which function to maintain awake, alert and active states required for performance of goal-directed activities essential for survival, including food seeking. Existing anatomical and functional evidence suggests the highly-conserved neuropeptide, relaxin-3, which signals via its cognate Gi/o-protein coupled receptor, RXFP3, contributes to behavioural arousal and feeding behaviour in rodents. In studies to investigate this possibility further, adult male C57BL/6J mice were treated with the selective RXFP3 antagonist peptides, R3(B1-22)R/I5(A) and R3(B1-22)R, and motivated food seeking and consumption was assessed as a reflective output of behavioural arousal.

Synthesis of fluorescent analogs of relaxin family peptides and their preliminary in vitro and in vivo characterization.

Relaxin, a heterodimeric polypeptide hormone, is a key regulator of collagen metabolism and multiple vascular control pathways in humans and rodents. Its actions are mediated via its cognate G-protein-coupled receptor, RXFP1 although it also "pharmacologically" activates RXFP2, the receptor for the related, insulin-like peptide 3 (INSL3), which has specific actions on reproduction and bone metabolism. Therefore, experimental tools to facilitate insights into the distinct biological actions of relaxin and INSL3 are required, particularly for studies of tissues containing both RXFP1 and RXFP2.

Pharmacological activation of RXFP3 is not orexigenic in C57BL/6J mice.

The neuropeptide relaxin-3 and its cognate G-protein-coupled receptor, RXFP3, have been implicated in the control of feeding behaviour in rats. For example, relaxin-3-positive projections and RXFP3 are present within hypothalamic feeding circuits, and icv injection of human relaxin-3 (-0.2 to 1.

Potential hypothalamic targets of relaxin-3 innervation: a perspective.

Relaxin-3 is a recently identified neuropeptide transmitter primarily expressed by neurons of the pontine nucleus incertus, which binds/activates the G(i/o)-protein coupled receptor, RXFP3. Functional studies have demonstrated that relaxin-3 modulates behavioural arousal in rodents, and although initial anatomical mapping studies have revealed relaxin-3-positive projections within several brain regions containing neurons that control behavioural arousal, further analysis of this topography has been hampered by the unavailability of a suitable specific RXFP3 antibody. In an effort to determine some of the neuron populations that relaxin-3 signalling directly modulates, we examined the distribution of relaxin-3 immunoreactive nerve fibres/terminals within the mouse lateral hypothalamus (LH) and ventrolateral preoptic area (VLPO), relative to elements containing protein markers for arousal-related neurons.

Viral-mediated delivery of an RXFP3 agonist into brain promotes arousal in mice.

Anatomical and functional studies of central relaxin-3/RXFP3 systems suggest they constitute an ascending arousal network. For example, relaxin-3 knockout mice display circadian hypoactivity compared to wild type littermate controls. In studies to explore the effect of chronic RXFP3 activation on behaviour, we engineered a lentiviral construct to constitutively secrete the RXFP3 agonist, R3/I5, and express a green fluorescent protein (GFP) marker in transduced cells.

Consequences of relaxin-3 null mutation in mice on food-entrainable arousal.

Relaxin-3/RXFP3 networks have been hypothesised to influence behavioural state based on their anatomical distribution and recent experimental findings in rat and mouse. Two arousal-related behaviours altered by changes in relaxin-3/RXFP3 signalling are feeding and voluntary running wheel activity. In particular, relaxin-3 null mutation (knockout) mice display a 'dark-phase hypoactivity' phenotype, reflected by reduced voluntary running wheel activity and increased sleeping behaviour, with no other major changes in basal behavioural profile.