Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention

Abstract

Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a "gene priming" phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

Keywords: EAAT3; N-acetylcysteine; drug addiction; gene priming; glutathione; s-adenosylmethionine; withdrawal.

Figure 1

Bidirectional regulation between transcriptional/epigenetic changes and metabolic homeostasis.

Figure 2

Methionine synthase acts as a redox switch. Methionine synthase contains a redox-active methylcobalamin cofactor. Under oxidative stress, this cofactor becomes oxidized, limiting methionine synthase activity. Under these conditions, homocysteine can be condensed with serine to form cystathionine and cysteine, which supports GSH synthesis. Only when cellular redox state is restored does the favorable GSH/GSSG ratio allow for the glutathionylation of oxidized cobalamin and methylation of the glutathionylcobalamin to reactivate the enzyme.

Figure 3

Effect of in vitro washout on redox equilibrium. Inhibition of cysteine uptake can alter cellular redox potential, resulting in adaptive changes in gene expression via epigenetic effects, which restore the redox equilibrium. However, in the absence of opioids during the washout phenomenon, these adaptive changes can lead to increased cysteine uptake as well as intracellular redox potential. A subsequent drug exposure with same or different drugs of abuse might also induce changes in the redox equilibrium further affecting the transcriptional regulatory mechanisms.

Figure 4

Gene priming. Epigenetic mechanisms mediate gene priming and desensitization under the influence of drugs of abuse, and that many of these changes are latent, meaning that they are not reflected by stable changes in steady-state mRNA levels. Instead, these changes would induce subsequent changes in chromatin structure, such that a later drug administration/washout would induce a given gene to a greater (primed) or lesser (desensitized) extent based on the epigenetic modifications induced by previous chronic drug exposure. A, acetylation; M, methylation; P, phosphorylation; pol II, RNA polymerase II.

Figure 5

Summary: Redox-based epigenetic signaling. Drugs of abuse alter cysteine uptake, affecting GSH synthesis, which shifts redox status and the reducing potential. This shift affects methionine synthase (MS) activity further affecting the probability of DNA methylation i.e., epigenetic changes, subsequently inducing changes in gene transcription or gene inducibility. If a repeated stimuli occurs, it results in altered gene transcription. This eventually affects the protein expression and consequently neuronal functionality and phenotype. Dotted line indicates that, neuronal activity can also redox status by altering the levels of ROS produced.