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

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.