Epigenetic regulation of adenosine A2A and dopamine D2 receptor gene transcription on compulsive food consumption.

Satisfactory treatments for eating disorders, such as binge eating disorder and bulimia nervosa, are not available at present. Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the adenosine A Receptor (A AR) and dopamine D2 (D2R) gene. Understanding the nature of genetic and epigenetic interactions in regulating individual risk of developing an eating disorder, might be helpful in search for new pharmacotherapeutic treatments. The animal model included 4 groups (rats fed normally, and then stressed or not, rats exposed to cycles of restriction/refeeding, and then stressed or not). Gene expression analysis carried out on the amygdala complex of stressed and restricted rats (R + S) revealed a significant increase of A AR and D2R mRNA when compared to non-stressed and not restricted (NR + NS) rats. Administration of the A AR agonist (VT 7) induced in R + S rats a significant increase of A AR and D2R mRNA levels when compared to control group, whereas a significant decrease in rats pre-treated with the A AR antagonist (ANR 94) was observed. Pyrosequencing analysis revealed a significant reduction of the % of DNA methylation at A AR promoter region in R + S compared to the NR + NS animals. We did not find any difference in D2R DNA methylation among different groups. Significant changes in the DNA methylation status of A AR promoter were found in R + S rats after administration of VT 7 or ANR 94. We observed a decrease of DNA methylation in VT 7 treated rats and a hypermethylation in ANR 94 rats with respect to the control group. The increase in A AR mRNA observed in R + S rats could be due to a compensatory mechanism to counteract the effect of binge eating, suggesting that the A AR activation, inducing receptor gene up-regulation, could be relevant to reduce food consumption. We here demonstrated for the first time the epigenetic regulation of A AR in an animal model of binge eating. Overall, our findings suggest that stress associated with food restriction promotes alterations in critical genes for feeding and reward circuitry, that influences food intake and stressrelated behaviours. These changes seem to be partially driven by epigenetic mechanisms promoting increased sensitivity of stress pathways that alter reward circuitry. It is possible that the brain develops strategies (namely, A AR DNA methylation) to guard against the likelihood that stress and restriction experiences would promote subsequent binge eating behaviours. Moreover, we confirm that A AR agonists may potentially be useful pharmacological agents to control binge eating via modulation of A AR and D2R gene transcription.