Abstract

Targeting DNA Methylation in Treatment of Behavioural and Mental Disorders; Lessons from Cancer

Moshe Szyf, Professor, McGill University

Insights into the epigenetic mechanisms that control gene expression in the CNS, and their role in neuropsychiatric disorders, are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. DNA methylation alterations are involved in the “incubation” of craving in a rat model of cocaine addiction. Intra-NAc injections of a DNA methyltransferase inhibitor RG108 that was paired with the cue abolished cue-induced cocaine seeking on day 30 and the effect remained up to 1 month after treatment. We then targeted two proteins whose genes were demethylated by RG108  estrogen receptor 1 (ESR1) and cyclin-dependent kinase 5 (CDK5). Treatment with the ESR1 agonist propyl pyrazole triol (PPT; 10nM) or the CDK5 inhibitior roscovitine on day 30 of withdrawal significantly decreased cue-induced cocaine seeking. These results support the use of combination of DNA demethylating agents and behavioral intervention in treating addiction.