Epigenetic regulation of the endocannbinoid system in Activity-based model of Anorexia nervosa.

Aims: Anorexia nervosa (AN) is a psychiatric disorder characterized by dramatic reduction in caloric intake by excessive dieting and irrational fears of gaining weight, often accompained by over-exercise. It has the highest mortality rate among psychiatric illnesses with no efficient pharmacological treatment available. Numerous studies have proven the role of the endocannabinoid system (ECS) in the regulation of feeding behaviour and its impaired signaling in AN, making it a promising target for disease treatment. Methods: Activity-based anorexia (ABA) is a bio-behavioural phenomenon that mimics key sympotms of AN in rodents where animals housed with running wheels and subjected to daily food restriction show paradoxical reductions in food intake and increases in running wheel activity. We investigated the transcriptional regulation of endocannabinoid system genes in the onset and progression of AN studying in ABA rat model two critical time-point: 3 days and 6 days. Results: Among ECS genes components, we observed a selective down-regulation of cannabinoid type-1 receptor gene (Cnr1) after 6 days ABA induction period in rats nucleus accumbens. Consistently, pyrosequencing has revealed increased DNA methylation levels at Cnr1 promoter. No changes were observed in other relevant brain regions studied (i.e. prefrontal cortex and hyothalamus) for any of ECS genes, besides a down-regulation again of Cnr1 in the hypothalamus. Conclusion: Our findings demonstrate selective and time-dependent epigenetic modulation of Cnr1 in ABA rats in relevant brain regions and therefore support the central role played by Cnr1 in food intake.