Naturally motivated behaviors, such as female sexual behavior, activate neural circuits that in turn mediate the rewarding aspects of the behavior. Activation of the mesocorticolimbic dopamine system by repeated sexual experience leads to long-term changes in behavioral, cellular, and structural plasticity. Specifically, we have found that a uniquely stable transcription factor, deltaFosB, accumulates in the core of the nucleus accumbens (NAc) following repeated sexual experience. To further determine the role of deltaFosB in sexual reward, we virally overexpressed deltaFosB in the NAc of female Syrian hamsters and tested them in a conditioned place preference paradigm. Overexpression of deltaFosB in the NAc resulted in enhanced sexual reward and improved copulatory efficiency with a male compared to control females overexpressing green fluorescent protein. Having established a role for this transcription factor in sexual reward, we next wanted to analyze how repeated sexual experience affected the gene expression of targets of deltaFosB mediated transcription in a limbic circuit. Repeated sexual experience resulted in a significant increase in mRNA expression of only one target of deltaFosB mediated transcription, the GluA2 subunit of the AMPA receptor in the NAc. Interested in the implications of increased GluA2 expression in the NAc on cellular excitability, we decided to pursue this research by determining whether total protein of GluA2 and GluA1 subunits of the AMPA receptor or their trafficking was differentially affected by repeated sexual experience. In contrast to the published changes in both total protein and receptor trafficking reported in the drug addiction literature, our results indicate that neither of these measures are affected by sexual experience, possibly indicating why natural motivated behaviors are typically not addictive. These results demonstrate that deltaFosB is important in mediating the rewarding consequences of female sexual behavior, and through its transcriptional activity alters gene expression that may underlie the consequent long-term behavioral, cellular and structural plasticity.