Wang Xiao-Fei, Bi Guo-Hua, He Yi, Yang Hong-Ju, Gao Jun-Tao, Okunola-Bakare Oluyomi M, Slack Rachel D, Gardner Eliot L, Xi Zheng-Xiong, Newman Amy Hauck
Neuropsychopharmacology Section, Molecular Target and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Neuropsychopharmacology. 2015 Jun;40(7):1762-71. doi: 10.1038/npp.2015.24. Epub 2015 Jan 23.
(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.
（±）-莫达非尼（MOD）在临床上用于治疗睡眠障碍，并已被研究作为治疗精神兴奋剂成瘾的潜在药物。然而，（±）-MOD对成瘾的治疗效果尚无定论。在此，我们使用自我给药动物模型和体内微透析技术，研究R-莫达非尼（R-MOD）和S-莫达非尼（S-MOD）对尼古丁摄取和觅药行为的药理作用及其作用机制。我们发现，在长-伊文斯大鼠中，R-MOD在减弱尼古丁自我给药方面比S-MOD更有效。由于长-伊文斯大鼠对尼古丁没有强烈的复吸反应，我们使用了对尼古丁复吸反应比长-伊文斯大鼠高得多的嗜酒大鼠（P大鼠）。我们发现，R-MOD显著抑制P大鼠静脉注射尼古丁的自我给药、尼古丁诱导的复吸以及尼古丁相关线索诱导的觅药行为。单独使用R-MOD既不能维持先前自我给药尼古丁的P大鼠的自我给药行为，也不能恢复已消退的尼古丁觅药行为。体内脑微透析试验表明，单独使用R-MOD可使细胞外多巴胺（DA）缓慢出现中度增加。在未接触尼古丁和自我给药尼古丁的大鼠中，用R-MOD预处理均能剂量依赖性地阻断尼古丁诱导的伏隔核（NAc）多巴胺（DA）释放，提示存在一种依赖DA的机制来减轻尼古丁的作用。总之，本研究结果支持进一步研究R-MOD用于治疗人类尼古丁依赖。
