Changes of BDNF exon IV DNA methylation are associated with methamphetamine dependence

Abstract

Aim: We investigated DNA methylation of BDNF in methamphetamine (METH) dependence in humans and an animal model. Materials & methods:BDNF methylation at exon IV was determined by pyrosequencing of blood DNA from METH-dependent and control subjects, and from rat brain following an escalating dose of METH or vehicle. Bdnf expression was determined in rat brain. Results:BDNF methylation was increased in human METH dependence, greatest in subjects with psychosis and in prefrontal cortex of METH-administered rats; rat hippocampus showed reduced Bdnf methylation and increased gene expression. Conclusion:BDNF methylation is abnormal in human METH dependence, especially METH-dependent psychosis, and in METH-administered rats. This may influence BDNF expression and contribute to the neurotoxic effects of METH exposure.

Lay abstract

The effects of methamphetamine (METH), an addictive psychostimulant drug, on changes of DNA methylation of an important regulator of neuronal survival, BDNF, were examined in blood of METH-dependent patients and in the brain of METH-administered rats. BDNF methylation was increased in patients and in the prefrontal cortex of METH-administered rats, while rat hippocampus showed a reduction of Bdnf methylation, with an equivalent increase in gene expression. The methylation increases in humans were greatest in those with a METH-induced psychosis. Although a relationship between Bdnf methylation and its expression has not been proven, changes of BDNF DNA methylation are associated with METH dependence, especially METH-dependent psychosis, suggesting that METH neurotoxicity may relate to the effects of changes in BDNF methylation.

Keywords: :

• BDNF
• DNA methylation
• drug dependence
• drug-induced psychosis
• gene expression
• methamphetamine
• psychosis
• rs6265

Acknowledgments

The authors acknowledge all participants who were involved in this study as well as the Central Correctional Institution for Drug Addicts, Bangkok, Thailand. The authors appreciate the Biomolecular Sciences Research Centre, Faculty of Health and Wellbeing, Sheffield Hallam University, UK and the Department of Anatomy, Faculty of Medical Sciences, Naresuan University for places and facility supports.

Financial & competing interests disclosure

This study was financially supported by the Naresuan University Research Fund for S Nudmamud-Thanoi and S Thanoi and Newton Fund-TRF grant for supervisors for S Nudmamud-Thanoi. S Iamjan was financially supported by the Royal Golden Jubilee PhD program (grant no. PHD/0247/2553) and Newton Fund-TRF PhD program-placement for scholars 2016/17 (British Council). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.