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

PLoS One. 2015 Apr 7;10(4):e0122504. doi: 10.1371/journal.pone.0122504. eCollection 2015.


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. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6JRXFP3TM1/DGen) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Dehydrogenase / metabolism
  • Alcohol Drinking
  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Ethanol / metabolism
  • Feeding Behavior / physiology*
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Saccharin
  • Signal Transduction
  • Stress, Physiological*


  • Receptors, G-Protein-Coupled
  • SALPR protein, mouse
  • Ethanol
  • Alcohol Dehydrogenase
  • Aldehyde Dehydrogenase
  • Saccharin

Grant support

This research was supported by a National Health and Medical Research Council (NHMRC) of Australia project grant (1021227 to ALG and AJL) and NHMRC (Australia) Research Fellowships (1005985 and 1020737) to ALG and AJL; a grant from the Pratt and Besen Foundations (ALG and AJL); and the Victorian Government's Operational Infrastructure Support Program. AWW was the recipient of a University of Melbourne International Postgraduate Research Scholarship (IPRS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.