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.
Highlights
Nicotine is a neuroactive alkaloid responsible for the development and maintenance of tobacco addiction (Stolerman and Jarvis, 1995; Pontieri et al, 1996; Merlo Pich et al, 1999)
As indicated, the prefrontal cortex is an important region in the glutamatergic decision-making system (Kalivas, 2009); while little is known about the effects of nicotine exposure on glutamate transporter-1 (GLT-1) and xCT expression, we examined the mRNA levels of both GLT-1 and xCT in the prefrontal cortex of rats following the reinstatement of oral consumption of a nicotine solution post-deprivation
Animals were given free-choice access of an oral nicotine solution prepared in water adulterated with sucrose, unlike the free-choice access of nicotine dissolved in distilled water that was used in the present work
Summary
Nicotine is a neuroactive alkaloid responsible for the development and maintenance of tobacco addiction (Stolerman and Jarvis, 1995; Pontieri et al, 1996; Merlo Pich et al, 1999). While tobacco is mostly smoked, oral intake of nicotine is well recognized. Current smoking cessation pharmacotherapies have largely targeted the nicotinic acetylcholine receptors (nAChRs), as the activation of these receptors mediates the early rewarding effects of tobacco (Coe et al, 2005; Rollema et al, 2007; Polosa and Benowitz, 2011). 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 and (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress
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