Laboratorio de Sı́ntesis Orgánica, Departamento de Quı́mica Orgánica, Facultad de Quı́mica, Universidad de la República, Montevideo 11200, Uruguay.
Departamento de Neurofarmacologı́a Experimental, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo 11600, Uruguay.
ACS Chem Neurosci. 2020 Jun 3;11(11):1661-1672. doi: 10.1021/acschemneuro.0c00152. Epub 2020 May 18.
Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 μM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine ∼0.5 μM, noribogaine ∼2.5 μM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.
一些传闻和人体开放性案例研究表明，迷幻生物碱伊博加因具有显著的抗成瘾作用。大量临床前证据表明伊博加因及其主要代谢物去甲伊博加因在物质使用障碍的啮齿动物模型中有效。与成瘾研究相反，伊博加因或去甲伊博加因在啮齿动物中与抑郁相关的作用以前没有被研究过。我们最近报道称，急性伊博加因给药会导致大鼠前额叶皮层中的脑源性神经营养因子 mRNA 水平长期增加，这使我们假设伊博加因可能会在大鼠中引发抗抑郁样作用。因此，我们使用强迫游泳试验（FST）表征了急性伊博加因和去甲伊博加因给药在大鼠中引起的行为效应（剂量和时间依赖性）（20 和 40 mg/kg i.p.，每种剂量单次注射）。我们还检查了伊博加因和去甲伊博加因的血浆和脑浓度与引起的行为反应之间的相关性。我们发现，伊博加因和去甲伊博加因诱导了剂量和时间依赖性的抗抑郁样作用，而动物的运动活动没有明显变化。去甲伊博加因的 FST 效应是短暂的（30 分钟），与高脑浓度相关（估计游离药物 >8 μM），而伊博加因的抗抑郁样作用在 3 小时时显著。在这个时间点，伊博加因和去甲伊博加因都存在于大鼠的大脑中，浓度不足以单独产生相同的行为结果（伊博加因约 0.5 μM，去甲伊博加因约 2.5 μM）。我们的数据表明伊博加因和去甲伊博加因的抗抑郁样作用是由多药理学机制支撑的。
