Relaxin-3 mRNA levels in nucleus incertus correlate with alcohol and sucrose intake in rats

The fulltext of this publication will be made publicly available after relevant embargo periods have lapsed and associated copyright clearances obtained.Full text Embargoed until: 2015-07-01BACKGROUND: Chronic alcohol intake produces multiple neuroadaptive changes, including up- and down-regulation of neuropeptides and receptors. There are widespread projections of relaxin-3 containing neurons to, and abundant relaxin family peptide 3 receptor (RXFP3) expression within, brain regions involved in modulating alcohol intake. Recently we demonstrated the involvement of relaxin-3/RXFP3 signalling in alcohol-seeking in rats; therefore in this study we examined whether relaxin-3 and/or RXFP3 expression were altered by chronic alcohol intake in alcohol-preferring iP rats. METHODS: Expression of relaxin-3 mRNA in the hindbrain nucleus incertus and RXFP3 radioligand binding levels in discrete forebrain regions were investigated following voluntary intake of alcohol or sucrose for 12 weeks, with a 2 day washout, using quantitative in situ hybridisation histochemistry and in vitro receptor autoradiography, respectively, in cohorts of adult, male iP rats. RESULTS: Levels of relaxin-3 mRNA in the hindbrain nucleus incertus were positively correlated with the level of intake of both alcohol (r(12)=0.59, p=0.03) and sucrose (r(7)=0.70, p=0.04) in iP rats. Dense binding of the RXFP3-selective radioligand, [(125)]-R3/I5, was detected in hypothalamic and extrahypothalamic sites, but no significant changes in the density of RXFP3 were observed in the brain regions quantified following chronic sucrose or ethanol intake. CONCLUSIONS: Our findings suggest high endogenous relaxin-3 expression may be associated with higher intake of rewarding substances, rather than its expression being regulated in response to their intake, consistent with an active role for the relaxin-3/RXFP3 system in modulating ingestive and alcohol-related behaviours

Relaxin-3/RXFP3 system regulates alcohol-seeking

Fulltext embargoed for: 6 months post date of publicationRelapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased self-administration of alcohol in a dose-related manner and attenuated cue- and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of reward-seeking