Targeting redox regulation to treat substance use disorder using N‐acetylcysteine

Abstract

Substance use disorder (SUD) is a chronic relapsing disorder characterized by transitioning from acute drug reward to compulsive drug use. Despite the heavy personal and societal burden of SUDs, current treatments are limited and unsatisfactory. For this reason, a deeper understanding of the mechanisms underlying addiction is required. Altered redox status, primarily due to drug-induced increases in dopamine metabolism, is a unifying feature of abused substances. In recent years, knowledge of the effects of oxidative stress in the nervous system has evolved from strictly neurotoxic to include a more nuanced role in redox-sensitive signaling. More specifically, S-glutathionylation, a redox-sensitive post-translational modification, has been suggested to influence the response to drugs of abuse. In this review we will examine the evidence for redox-mediating drugs as therapeutic tools focusing on N-acetylcysteine as a treatment for cocaine addiction. We will conclude by suggesting future research directions that may further advance this field.

Keywords: N-acetylcysteine; S-glutathionylation; addiction; antioxidant; cocaine; post-translational modification.

Figure 1.

The oxidation of dopamine produces reactive oxygen species. At physiological concentrations, dopamine is subjected to oxidative deamination via MAO, to produce DOPAL and hydrogen peroxide, which may in turn react with Fe²⁺ to form hydroxyl radicals via the Fenton reaction. Following drug use, the elevated concentrations of dopamine may promote spontaneous oxidation of the catechol moiety to form dopamine o-quinones and superoxide radicals. The reaction of dopamine o-quinone with cysteine to form 5-S-cysteinyl-dopamine may in turn generate peroxide and superoxide radicals. Increasing levels of hydrogen peroxide and superoxide radicals further promotes dopamine auto-oxidation. Thus, the oxidative metabolism of dopamine may induce oxidative stress. Unpaired electrons are shown in red. DOPAL = 3,4-dihydroxyphenylacetaldehyde; MAO = monoamine oxidase.

Figure 2.

The post-translational modification S-glutathionylation describes the reversible conjugation of glutathione (GSH) to low pK_a cysteine residues (P-SH) under conditions of oxidative stress, such as those produced by drugs of abuse. In this way, S-glutathionylated proteins (P-SSG) are protected from irreversible oxidation and subsequent degradation. The forward reaction is catalyzed by glutaredoxin and members of the glutathione S-transferase (GST) family. The reverse reaction occurs following a return to more reducing conditions and may occur spontaneously or via catalysis by glutaredoxin, thioredoxin and sulfiredoxin. S-glutathionylation may also affect protein structure and function.

Figure 3.

N-acetylcysteine (NAC) may impact S-glutathionylation. The deacetylation of NAC produces cysteine that dimerizes to cystine, which may be exchanged for glutamate via system x_c-. The subsequent increase in extracellular glutamate helps to restore the drug-induced reduction in glutamatergic tone. NAC also increases levels of the antioxidant glutathione, which when conjugated to low pK_a cysteine residues under oxidative conditions, results in S-glutathionylation. This reversible post-translational modification may impact protein structure and function including those involved in drug-related behavior, plasticity and signaling. GSH = glutathione; GSTM = glutathione S-transferase mu, GSTP = glutathione S-transferase pi; -SH = reduced thiol; -SSG = oxidized thiol