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.

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…Another avenue for enhancing specificity derives from accumulating knowledge of the effects of oxidative stress in the nervous system, evolving from strictly neurotoxic to including a more nuanced role in redox‐sensitive signalling. Evidence for redox‐mediating drugs as therapeutic tools (focusing on N‐acetylcysteine as a treatment for cocaine addiction) is presented as one example (Womersley et al ., ).…”

Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity. A Systematic Review

“…Reactive oxygen species as a result of dopamine transmission Cocaine cardiotoxicity involves various direct and indirect mechanisms such as blockage of sodium, and potassium channels and altered calcium ow across the myocyte cell membrane and inhibition of reuptake and increased levels of the neurotransmitters dopamine, and norepinephrine. Acute toxicity and drug dependence have been associated with impaired energy and amino acid metabolism, oxidative stress increased levels, and altered dopamine neurotransmission [Womersley et al 2019]. Elevated levels of plasma and interstitial catecholamines and generated ROS and RNS cause prolonged adrenergic stress and a series of adverse effects with signi cant cardiotoxicity detrimental to the cardiovascular system [Costa et al 2011].…”

Evaluation of Cysteine Metabolism in the Rat Liver and Kidney Following Intravenous Cocaine Administration and Abstinence

“…The latter results clearly suggest that, in the kidney, cocaine shifts Cys metabolism towards the anaerobic route, yielding compounds with sulfane sulfur, which possesses regulatory and antioxidant properties. It has also been documented that N -acetylcysteine (NAC), which is a precursor of both Cys and sulfane sulfur, produced a significant decline in cocaine-induced reinstatement in an animal model [ 18 , 19 , 20 , 21 ].…”