Abstract
Epigenetic modifications such as DNA methylation play important roles in regulating gene expression and may mediate neuroplasticity and lead to drug-induced aberrant behaviors. Although several brain regions and neurobiological mechanisms have been suggested to be involved in these processes, there is remarkably little known about the effects of DNA methylation on heroin-seeking behavior. Using a Sprague-Dawley rat model, we show that heroin self-administration resulted in gamma-aminobutyric acid type A receptor subunit delta (GABRD) gene hypomethylation, which was associated with transcriptional upregulation of GABRD in the nucleus accumbens (NAc). Systemic l-methionine (MET) administration significantly strengthened the reinstatement of heroin-seeking behavior induced by heroin priming, whereas intra-NAc injections of the DNA methyltransferase (DNMT) inhibitor 5-aza-2′-deoxycytidine (5-Aza-dC) had the opposite effect on heroin-seeking. Meanwhile, 5-Aza-dC treatment decreased DNA methylation and upregulated the expression of GABRD in the NAc, whereas MET had the opposite effect. Our results also reveal that 5-Aza-dC might alter the methylation landscape of the GABRD gene by directly repressing DNMT1 and DNMT3A expression. Furthermore, reinstatement of heroin-seeking behavior was significantly inhibited by directly overexpressing GABRD and remarkably reinforced by GABRD gene silencing in the NAc. Collectively, these results suggest that targeting the GABRD gene and its methylation might represent a novel pharmacological strategy for treating heroin addiction and relapse.
Highlights
Heroin addiction is a chronic and relapsing brain disorder characterized by compulsive drugseeking and the negative emotional state of withdrawal
We revealed that heroin self-administration induced global DNA methylation changes in the nucleus accumbens (NAc)
Subsequent validation by pyrosequencing verified that DNA methylation at the gamma-aminobutyric acid type A receptor subunit delta (GABRD) CpG island significantly decreased and that GABR pi (GABRP) promoter methylation significantly increased in the NAc of heroin self-administration rats
Summary
Heroin addiction is a chronic and relapsing brain disorder characterized by compulsive drugseeking and the negative emotional state of withdrawal. Relapse to drug-seeking after abstinence has long been a challenge in the treatment of heroin addiction. Heroin addiction is characterized by specific behavioral alterations, indicating long-lasting alterations in gene and protein expression within specific reward-related brain regions. Accumulating evidence has demonstrated that epigenetic mechanisms such as DNA methylation regulate drug-induced gene expression profiles and enduring behavioral phenotypes (Nestler, 2014; Kalda and Zharkovsky, 2015). Recent data suggest that altered DNA methylation may indicate the changed gene expression. Epigenetic modifications may be a critical molecular mechanism that indicated the enduring addictionrelated changes in brain plasticity (Robison and Nestler, 2011; Godino et al, 2015; Massart et al, 2015)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call