Natural rewards and psychostimulants cause similar neural plasticity in the nucleus accumbens (NAc). In addition, sexual experience in male rats causes increased locomotor activity and conditioned place preference (CPP) induced by d-Amphetamine (amph). The latter is dependent on a period of abstinence from sexual reward. In this study, the role of mGluR5 activation in the NAc for expression of mating and the cross-sensitizing effects of sexual experience was tested. First, intra-NAc infusions of mGluR5 antagonists MPEP (1 or 10 μg/μL) or (1 μg/μL) 15 min prior to mating during 4 daily sessions had no effect on male rat sexual behavior. Subsequently, these sexually experienced males were tested for amph-induced locomotor activity and CPP after one week of abstinence from sexual reward. In addition, sexually naïve males that received MPEP, MTEP or vehicle infusions prior to 4 daily handling sessions were included. Cross-sensitization of locomotion or CPP was not prevented by NAc mGluR5 antagonism during acquisition of sexual experience. Instead, sexually naive animals that received NAc mGluR5 antagonists without mating demonstrated sensitized amph-induced locomotor responses and enhanced CPP on par with sexually experienced males. Finally, we showed that sexual experience caused prolonged down-regulation of mGluR5 protein in the NAc, dependent on abstinence from sexual behavior. Together, these findings suggest that mGluR5 activation in the NAc is not essential for the expression of mating, but that experience-induced reduction in mGluR5 protein may contribute to the cross-sensitization of amph responses by sexual experience and abstinence.