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

Abstract

BackgroundNicotine is the major addictive component of cigarette smoke and the prime culprit of the failure to quit smoking. Common elements perpetuating the use of addictive drugs are (i) cues associated with the setting in which drug was used and (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress.AimsThe present study assessed the effect of the coadministration of the antioxidant N-acetylcysteine (NAC) plus the anti-inflammatory acetylsalicylic acid (ASA) on oral nicotine reinstatement intake following a post-deprivation re-access in female rats that had chronically and voluntarily consumed a nicotine solution orally. The nicotine-induced oxidative stress and neuroinflammation in the hippocampus and its effects on the glutamate transporters GLT-1 and XCT mRNA levels in prefrontal cortex were also analyzed.ResultsThe oral coadministration of NAC (40 mg/kg/day) and ASA (15 mg/kg/day) inhibited by 85% of the oral nicotine reinstatement intake compared to control (vehicle), showing an additive effect of both drugs. Acetylsalicylic acid and N-acetylcysteine normalized hippocampal oxidative stress and blunted the hippocampal neuroinflammation observed upon oral nicotine reinstatement. Nicotine downregulated GLT-1 and xCT gene expression in the prefrontal cortex, an effect reversed by N-acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of N-acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.ConclusionNicotine reinstatement, following post-deprivation of chronic oral nicotine intake, downregulates the mRNA levels of GLT-1 and xCT transporters, an effect reversed by the coadministration of N-acetylcysteine and acetylsalicylic acid, leading to a marked inhibition of nicotine intake. The combination of these drugs may constitute a valuable adjunct in the treatment of nicotine-dependent behaviors.

Assessing combined effects of varenicline and N‐acetylcysteine on reducing nicotine seeking in rats

“…NAC, however, restores resting‐state functional connectivity in this network, 51 and restoration of frontostriatal connectivity is associated with reduced craving and smoking relapse compared with placebo‐treated smokers 30 . Further, a recent study also found that NAC treatment normalized nicotine‐induced downregulation of GLT‐1 and glutamate cysteine exchanger expression in the prefrontal cortex of rats 52 . Thus, it appears that the combined VRN + NAC treatment approach proposed here confers effects in these separable circuits to reduce reinforcement and relapse of nicotine seeking.…”

“…30 Further, a recent study also found that NAC treatment normalized nicotine-induced downregulation of GLT-1 and glutamate cysteine exchanger expression in the prefrontal cortex of rats. 52 Thus, it appears that the combined VRN + NAC treatment approach proposed here confers effects in these separable circuits to reduce reinforcement and relapse of nicotine seeking.…”

Acetylsalicylic acid reduces cigarette smoke withdrawal-induced anxiety in rats via modulating the expression of NFĸB, GLT-1, and xCT

“…Chronic nicotine consumption causes oxidative stress, which inhibits astrocyte glutamate transporters ( Berríos-Cárcamo et al, 2020 ). Recent research suggests that cue-induced restoration of nicotine self-administration and chronic nicotine exposure in rats are linked with higher TNF-α levels in the PFC and NAc ( Namba, 2019 ; Quintanilla et al, 2021 ).…”

“…ASA works to reduce the synthesis of prostaglandin E2 and pro-inflammatory cytokines by inhibiting the cyclooxygenase COX-1 and COX-2 enzymes ( Israel et al, 2021 ). Importantly, ASA upregulates GLT-1 protein levels after chronic ethanol intake and chronic oral nicotine intake, blocks relapse to binge drinking, and inhibits nicotine reinstatement in female rats ( Quintanilla et al, 2020 ; Israel et al, 2021 ). ASA also increases GLT-1 levels in the PFC ( Quintanilla et al, 2021 ) and may also suppress the NF-κB pathway ( Dąbek et al, 2010 ).…”

“…Importantly, ASA upregulates GLT-1 protein levels after chronic ethanol intake and chronic oral nicotine intake, blocks relapse to binge drinking, and inhibits nicotine reinstatement in female rats ( Quintanilla et al, 2020 ; Israel et al, 2021 ). ASA also increases GLT-1 levels in the PFC ( Quintanilla et al, 2021 ) and may also suppress the NF-κB pathway ( Dąbek et al, 2010 ). To explore the relationships between neuroimmune states, glutamatergic systems, and neuroplasticity, this study investigated the effect of cigarette smoke exposure and treatment with ASA on NF-κB, GLT-1, and xCT relative mRNA and protein levels in mesocorticolimbic brain regions, i.e., the PFC and NAc.…”