Relaxin-3 receptor (Rxfp3) gene deletion reduces operant sucrose- but not alcohol-responding in mice

Genes Brain Behav. 2015 Nov;14(8):625-34. doi: 10.1111/gbb.12239. Epub 2015 Oct 14.


The pervasive use of refined sugars in highly accessible, palatable foods and persistent exposure to reinforcing food-associated cues has contributed to overconsumption of sugar-rich diets and the current obesity epidemic in Western society. We have shown previously that brain relaxin-3 mRNA levels positively correlate with sucrose and alcohol intake, and that central antagonism of relaxin-3 receptors (RXFP3) attenuates alcohol self-administration and alcohol-seeking in rats, but food-seeking behaviour and palatable food consumption in mice. To further examine the relationship between motivated appetitive behaviours and relaxin-3/RXFP3 signalling, we investigated the effect of Rxfp3 gene deletion in C57BL/6J mice on sucrose and alcohol self-administration and cue-induced reinstatement (RNST) of sucrose- and alcohol-seeking. Acquisition and maintenance of sucrose and alcohol self-administration was assessed in male wild-type (WT) and Rxfp3 knockout (KO) (C57BL/6J(RXFP3TM1) (/) (DGen) ) littermate mice using fixed ratio (FR) schedules of reinforcement. Mice were subsequently challenged with a progressive ratio (PR) test to measure motivation and, following extinction training, re-exposed to reward-associated cues to evaluate RNST of active lever-responding. Wild-type and Rxfp3 KO mice displayed similar acquisition of FR1 sucrose self-administration, but Rxfp3 KO mice responded less when the instrumental requirement was increased to FR3. These mice also showed a lower breakpoint for sucrose and attenuated cue-induced RNST of sucrose-seeking. Notably, no marked genotype differences in alcohol-responding were observed. In mice, endogenous relaxin-3/RXFP3 signalling promotes self-administration of sucrose under high response requirements and cue-induced RNST of sucrose-seeking, but does not apparently regulate motivation to consume alcohol or alcohol-seeking behaviour.

Keywords: Alcohol; cue-induced reinstatement; operant; progressive ratio; relaxin-3/RXFP3; sucrose-seeking.

MeSH terms

  • Alcohol Drinking / genetics
  • Animals
  • Appetitive Behavior / physiology
  • Conditioning, Operant / physiology*
  • Ethanol / administration & dosage*
  • Gene Deletion
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motivation / genetics
  • Motivation / physiology
  • Random Allocation
  • Receptors, G-Protein-Coupled / genetics*
  • Relaxin / deficiency*
  • Relaxin / genetics
  • Self Administration
  • Sucrose / administration & dosage*


  • Receptors, G-Protein-Coupled
  • relaxin-3 protein, mouse
  • Ethanol
  • Sucrose
  • Relaxin