Supervisors: vanemteadur Anti Kalda (TÜ farmakoloogia osakond) ja professor Aleksander Žarkovski
(TÜ farmakoloogia osakond).
Opponent dotsent Markus Mikael Forsberg, PhD (Ida-Soome Ülikool)
Drug addiction is a chronic relapsing disorder characterised by a pattern of compulsive drug seeking and taking behaviour despite severe adverse consequences. Prolonged abuse of drugs, such as psychostimulants, may contribute to behavioural abnormalities that can last for months or even years after discontinuing drug consumption. Repeated administration of psychostimulants (such as cocaine) induces an enhanced behavioural response to subsequent drug exposure, a phenomenon known as psychomotor or behavioural sensitisation. Psychostimulant-induced behavioural sensitisation in rodents provides a model for addictive behaviours, such as those associated with craving and relapse, and for the psychotic complications of psychostimulant abuse. Behavioural sensitisation is remarkably persistent phenomenon. In rodents, it can persist from months to years after drug treatment is discontinued. Persistent behavioural sensitisation indicates that drug-induced short- and long-term changes in gene expression may be involved. Accumulating data suggest that epigenetic mechanisms, such as DNA methylation (catalysed by DNA methyltransferases - DNMTs), are critical regulators of persistent gene expression changes and may be related to behavioural disorders. The aim of this study was to investigate the role of DNA methylation in the development of cocaine-induced behavioural sensitisation in mice and rats. Our data demonstrated that cocaine treatment caused a dynamic increase in Dnmt3a and Dnmt3b expression levels in the nucleus accumbens (NAc) and hippocampus of adult mice; induced both DNA methylation/demethylation in the promoter regions of the selected genes; and intracerebroventricular treatment with the DNMT inhibitor zebularine normalised hypermethylated gene transcription in the NAc of adult mice and delayed the development of cocaine-induced behavioural sensitisation. We also found that environmental factors, such as methyl group donor S-adenosylmethionine (SAM) and early life stress, may promote, via DNA methylation, the development of psychostimulant-induced drug addiction in mice and rats.