AUTHOR=Quintanilla María Elena , Morales Paola , Ezquer Fernando , Ezquer Marcelo , Herrera-Marschitz Mario , Israel Yedy 

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

JOURNAL=Frontiers in Behavioral Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2021

URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2020.617418

DOI=10.3389/fnbeh.2020.617418

ISSN=1662-5153

ABSTRACT=ABSTRACT
Background. Nicotine 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; (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress.
Aims. The present study assessed the effect of the co-administration 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.
Results. The oral co-administration of NAC; (40 mg/kg/day) and ASA (15 mg/kg/day) inhibited by 85% 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 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. 
Conclusion. Nicotine reinstatement, following post-deprivation of chronic oral nicotine intake downregulates the mRNA levels of GLT-1 and xCT transporters, an effect reversed by the co-administration 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