Glick S D, Maisonneuve I S
Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA.
Ann N Y Acad Sci. 1998 May 30;844:214-26.
Ibogaine, an alkaloid extracted from Tabemanthe iboga, is being studied as a potential long-acting treatment for oploid and stimulant abuse as well as for alcoholism and smoking. Studies in this laboratory have used animal models to characterize ibogaine's interactions with drugs of abuse, and to investigate the mechanisms responsible. Ibogaine, as well as its metabolite, noribogaine, can decrease both morphine and cocaine self-administration for several days in some rats; shorter-lasting effects appear to occur on ethanol and nicotine intake. Acutely, both ibogaine and noribogaine decrease extracellular levels of dopamine in the nucleus accumbens of rat brain. Ibogaine pretreatment (19 hours beforehand) blocks morphine-induced dopamine release and morphine-induced locomotor hyperactivity while, in contrast, it enhances similar effects of stimulants (cocaine and amphetamine). Ibogaine pretreatment also blocks nicotine-induced dopamine release. Both ibogaine and noribogaine bind to kappa opioid and N-methyl-D-aspartate (NMDA) receptors and to serotonin uptake sites; ibogaine also binds to sigma-2 and nicotinic receptors. The relative contributions of these actions are being assessed. Our ongoing studies in rats suggest that kappa agonist and NMDA antagonist actions contribute to ibogaine's effects on opioid and stimulant self-administration, while the serotonergic actions may be more important for ibogaine-induced decreases in alcohol intake. A nicotinic antagonist action may mediate ibogaine-induced reduction of nicotine preferences in rats. A sigma-2 action of ibogaine appears to mediate its neurotoxicity. Some effects of ibogaine (e.g., on morphine and cocaine self-administration, morphine-induced hyperactivity, cocaine-induced increases in nucleus accumbens dopamine) are mimicked by kappa agonist (U50,488) and/or a NMDA antagonist (MK-801). Moreover, a combination of a kappa antagonist and a NMDA agonist will partially reverse several of ibogaine's effects. Ibogaine's long-term effects may be mediated by slow release from fat tissue (where ibogaine is sequestered) and conversion to noribogaine. Different receptors, or combinations of receptors, may mediate interactions of ibogaine with different drugs of abuse.
伊波加因是从伊博格木中提取的一种生物碱，目前正作为一种潜在的长效治疗药物，用于治疗阿片类药物和兴奋剂滥用以及酗酒和吸烟问题。本实验室的研究使用动物模型来描述伊波加因与滥用药物的相互作用，并研究其作用机制。伊波加因及其代谢产物去甲伊波加因在一些大鼠中可使吗啡和可卡因的自我给药量减少数天；对乙醇和尼古丁摄入量的影响持续时间较短。急性给药时，伊波加因和去甲伊波加因均可降低大鼠脑伏隔核中多巴胺的细胞外水平。伊波加因预处理（提前19小时）可阻断吗啡诱导的多巴胺释放和吗啡诱导的运动性多动，而相比之下，它会增强兴奋剂（可卡因和苯丙胺）的类似作用。伊波加因预处理还可阻断尼古丁诱导的多巴胺释放。伊波加因和去甲伊波加因均与κ阿片受体、N-甲基-D-天冬氨酸（NMDA）受体以及5-羟色胺摄取位点结合；伊波加因还与σ-2受体和烟碱受体结合。目前正在评估这些作用的相对贡献。我们正在进行的大鼠研究表明，κ激动剂和NMDA拮抗剂的作用有助于伊波加因对阿片类药物和兴奋剂自我给药的影响，而5-羟色胺能作用可能对伊波加因引起的酒精摄入量减少更为重要。烟碱拮抗剂作用可能介导伊波加因诱导的大鼠对尼古丁偏好的降低。伊波加因的σ-2作用似乎介导了其神经毒性。伊波加因的一些作用（如对吗啡和可卡因自我给药、吗啡诱导的多动、可卡因诱导的伏隔核多巴胺增加）可被κ激动剂（U50,488）和/或NMDA拮抗剂（MK-801）模拟。此外，κ拮抗剂和NMDA激动剂的组合将部分逆转伊波加因的几种作用。伊波加因的长期作用可能是由脂肪组织（伊波加因在其中被隔离）的缓慢释放以及转化为去甲伊波加因介导的。不同的受体或受体组合可能介导伊波加因与不同滥用药物的相互作用。
