Quintanilla María Elena, Morales Paola, Ezquer Fernando, Ezquer Marcelo, Herrera-Marschitz Mario, Israel Yedy
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago, Chile.
Front Behav Neurosci. 2021 Feb 3;14:617418. doi: 10.3389/fnbeh.2020.617418. eCollection 2020.
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.
The present study assessed the effect of the coadministration of the antioxidant -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.
The 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 -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 -acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of -acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.
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 coadministration of -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.
尼古丁是香烟烟雾中的主要成瘾成分，也是戒烟失败的首要元凶。导致成瘾药物持续使用的常见因素包括：（i）与药物使用环境相关的线索；（ii）由谷氨酸能张力增加介导的复发/复吸；（iii）与药物诱导的神经炎症和氧化应激相关。
本研究评估了抗氧化剂N-乙酰半胱氨酸（NAC）与抗炎药乙酰水杨酸（ASA）联合给药对长期自愿口服尼古丁溶液的雌性大鼠在剥夺后重新接触尼古丁时口服尼古丁复吸摄入量的影响。还分析了尼古丁诱导的海马氧化应激和神经炎症及其对前额叶皮质中谷氨酸转运体GLT-1和xCT mRNA水平的影响。
与对照组（赋形剂）相比，口服NAC（40mg/kg/天）和ASA（15mg/kg/天）可使口服尼古丁复吸摄入量降低85%，显示出两种药物的相加作用。乙酰水杨酸和N-乙酰半胱氨酸可使海马氧化应激恢复正常，并减轻口服尼古丁复吸时观察到的海马神经炎症。尼古丁下调前额叶皮质中GLT-1和xCT基因的表达，N-乙酰半胱氨酸可逆转这一效应，而乙酰水杨酸可逆转尼古丁诱导的GLT-1基因表达下调。xCT转运体抑制剂柳氮磺胺吡啶可阻断N-乙酰半胱氨酸对慢性尼古丁摄入量的抑制作用。
长期口服尼古丁剥夺后，尼古丁复吸会下调GLT-1和xCT转运体的mRNA水平，N-乙酰半胱氨酸和乙酰水杨酸联合给药可逆转这一效应，从而显著抑制尼古丁摄入。这些药物的组合可能是治疗尼古丁依赖行为的有价值辅助手段。
