Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Abstract

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc− activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats

“…Oxidative stress (ROS) inhibits glutamate transport by the direct inhibition of GLT-1 activity ( Trotti et al, 1997 , 1998 ) and also by the formation of adducts of glutamate transporters with lipoperoxidation products like 4-hydroxynonenal and 4-hydroxyhexenal ( Schaur et al, 2015 ), while the pro-inflammatory cytokine TNFα leads to the downregulation of the GLT-1 mRNA level ( Szymocha et al, 2000 ; Wang et al, 2003 ; Sitcheran et al, 2005 ). Taken together, these studies support the growing view that conditions present in an oxidative-stress/neuroinflammation self-perpetuating cycle ( Berrios-Carcamo et al, 2020 ) disrupt glutamate homeostasis by impairing glutamate transport in areas involved in the brain reward system, increasing the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption ( Kalivas, 2009 ).…”

“…The above findings indicate (a) a nicotine-induced activation of microglia as associated with ROS production and (b) TNF-α increases, known to activate NADPH oxidase ( Kim et al, 2007 ; Basuroy et al, 2009 ) and generate hydrogen peroxide and mitochondrial superoxide ions ( Kastl et al, 2014 ). Combined, these studies suggest that oxidative stress and neuroinflammation are self-perpetuated in a vicious-like cycle, making relapse a protracted event ( Berrios-Carcamo et al, 2020 ).…”

“…Oxidative stress (and associated neuroinflammation), as induced by chronic nicotine intake, inhibits astrocyte glutamate transporters that regulate glutamate homeostasis ( Berrios-Carcamo et al, 2020 ). Previous research has established that alterations of glutamate homeostasis in the prefrontal cortex and nucleus accumbens contribute to the reinstatement of drug-seeking behavior ( Kalivas, 2009 ).…”

“…The likely mechanism of inhibition of the two glutamate transporters GLT-1 and xCT is an oxidation of their cysteine residues ( Trotti et al, 1997 , 1998 ; Berrios-Carcamo et al, 2020 ). Additionally, TNFα leads to the downregulation of GLT-1 gene expression ( Szymocha et al, 2000 ; Wang et al, 2003 ; Sitcheran et al, 2005 ).…”

CXCR4 inhibition with AMD3100 attenuates amphetamine induced locomotor activity in adolescent Long Evans male rats

“…Clinical evidence from abstinent lifetime cocaine users implicates CXCL12-CXCR4 and other proinflammatory substrates as predictors of cocaine symptom severity and suggests the use of these substrates as biomarkers for the development of intervention protocols for psychostimulant use disorders and psychiatric comorbidities [ 38 ]. Furthermore, clinical and rodent models demonstrate anti-inflammatory agents as effective therapies for psychiatric and substance use disorders [as reviewed by 39 , 40 ].…”