On 25 September at 14:15 via Microsoft Teams Mari Urb will defend her doctoral thesis "DNA methylation in the predisposition, expression and abstinence of cocaine addiction“.
Supervisors: Professor Anti Kalda (Institute of Biomedicine and Translational Medicine, University of Tartu) and Professor Tõnis Timmusk (Tallinn University of Technology).
Opponent: Lecturer Petteri Piepponen (Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland).
SUD is a brain disease, where a psychoactive substance triggers physical, psychological problems or decrease in social functioning. SUD develops progressively and causes persistent neurobiological changes that may endure after substance use has ceased. Repeated cocaine administration causes an enhanced behavioral response in rodents (behavioral sensitization) that models addictive behavior and psychotic complications of cocaine in humans. Early life stress is a risk factor for the development of SUD. Psychostimulants (e.g. cocaine) cause changes in gene expression that alter neuronal morphology, signaling and the functioning of neural circuits. DNA methylation is a cellular mechanism that mediates gene expression changes in response to environmental and developmental stimuli. The enzymes DNA methyltransferases perform DNA methylation.
The aim of the dissertation was to assess on behavioral and molecular level whether cocaine induced changes in DNA methylation may underlie individual sensitivity, expression and abstinence of substance abuse. Additional aim of the dissertation was to evaluate how stress affects DNA methylation in the brain.
The results showed that early life stress increases DNMT expression and enzyme activity in rodent brain via an intracellular signaling pathway of glucocorticoid receptor that may lead to persistent changes in gene expression and increased sensitivity to cocaine. We also found that repeated cocaine administration to mice increased DNMT activity in the expression and abstinence of behavioral sensitization and some cocaine-induced DNMT changes in the nucleus accumbens are similar to changes in mice leukocytes. Reduction in Dnmt3a gene expression increased behavioral sensitization, but not during abstinence, thus Dnmt3a has an important role during the development of SUD.
DNA methylation may be important in the development and abstinence phase of drug abuse to maintain changes in gene expression. DNMT activity may be a candidate for determining cocaine use after the drug has been metabolized.