The role of DNA methyltransferase activity in cocaine treatment and withdrawal in the nucleus accumbens of mice

Abstract

An increasing number of reports have provided crucial evidence that epigenetic modifications, such as DNA methylation, may be involved in initiating and establishing psychostimulant‐induced stable changes at the cellular level by coordinating the expression of gene networks, which then manifests as long‐term behavioral changes. In this study, we evaluated the enzyme activity of DNA methyltransferases (DNMTs) after cocaine treatment and during withdrawal. Furthermore, we studied how genetic or pharmacological inhibition of DNMTs in mouse nucleus accumbens (NAc) affects the induction and expression of cocaine‐induced behavioral sensitization. Our results showed that after silencing Dnmt3a in the NAc during the induction phase of cocaine‐induced sensitization, overall DNMT activity decreases, correlating negatively with behavioral sensitization. Reduced Dnmt3a mRNA during this phase was the largest contributing factor for decreased DNMT activity. Cocaine withdrawal and a challenge dose increased DNMT activity in the NAc, which was associated with the expression of behavioral sensitization. Long‐term selective Dnmt3a transcription silencing in the NAc did not alter DNMT activity or the expression of cocaine‐induced behavioral sensitization. However, bilateral intra‐NAc injection of a non‐specific inhibitor of DNMT (RG108) during withdrawal from cocaine decreased DNMT activity in the NAc and had a small effect on the expression of cocaine‐induced behavioral sensitization. Thus, cocaine treatment and withdrawal is associated with biphasic changes in DNMT activity in the NAc, and the expression of behavioral sensitization decreases with non‐selective inhibition of DNMT but not with selective silencing of Dnmt3a.

Cocaine-induced changes in behaviour and DNA methylation in rats are influenced by inter-individual differences in spontaneous exploratory activity

“…We suppose that this increase in Dnmt3b mRNA levels in the NAc is a regulatory mechanism and that DNMTs compensate for each other's functions. This speculation is supported by the reports that demonstrate that Dnmt3b functionally compensates for Dnmt1 deficiency in intestinal epithelium and Dnmt3a silencing in the NAc (Elliott et al, 2016;Urb et al, 2019). Comparable to Dnmt3b mRNA levels in the NAc, we found that RC exposure significantly increased the mRNA levels of Tet3 in the NAc of HE rats.…”

“…Accumulating data suggest that epigenetic modifications within brain reward circuits, for example, in nucleus accumbens (NAc), may be key regulators of the persistent changes in brain plasticity and gene expression related to addiction (Nestler, 2014). We and other groups have demonstrated that DNA methylation (DNAm), the addition of a methyl group to Position 5 of the cytosine (5-mC), plays a role in psychostimulant-induced changes in gene expression and behaviour (Anier et al, 2010(Anier et al, , 2018LaPlant et al, 2010;Massart et al, 2015;Nielsen et al, 2012;Pol Bodetto et al, 2013;Tian et al, 2012;Urb et al, 2019). In addition, studies have indicated that the lateral habenula (LHb) might play an important role in reward and drug addiction mechanisms (Jhou et al, 2013;Lecca et al, 2014;Matsumoto and Hikosaka, 2007;Shelton et al, 2016).…”

Behavioral Sensitization Induced by Methamphetamine Causes Differential Alterations in Gene Expression and Histone Acetylation of the Prefrontal Cortex in Rats

“…The enduring effects of these drugs, even after long periods of abstinence, have suggested the presence of persistent molecular events caused by transcriptional, epigenetic and translational changes [1] within addictionrelated brain regions [2], such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus. Notably, accumulating evidence has revealed an important role of epigenetic regulation in the effects of psychostimulants [3](e.g., cocaine [4,5]) and identi ed the involvement of modi cations of histones present in chromatin [6,7], DNA methylation [8,9], and DNA hydroxymethylation in the development of addiction. With respect to METH, however, only a few studies have investigated the epigenetic effects of these drugs, mainly focusing on the NAc and striatum [10][11][12][13][14].…”

Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes

“…Furthermore, acute and repeated cocaine treatment leads to the hypermethylation of fosB promoter associated CpG islands in the NAc. Additionally, Mari Urb et al [ 38 ] reported that the expression of DNMT-3b in the postnatal mouse brain is relatively low compared to that of DNMT-1 and DNMT-3a. Interestingly, acute (0.5–3 h) exposure to cocaine reduces the mRNA expression of DNMT-1 and DNMT-3a in the NAc, which indicates that cocaine regulates DNMT mRNA expression in a time-dependent manner [ 39 ].…”