EFFECTS OF IBOGA ALKALOIDS ON MORPHINE AND COCAINE SELF-ADMINISTRATION IN RATS - RELATIONSHIP TO TREMORIGENIC EFFECTS AND TO EFFECTS ON DOPAMINE RELEASE IN NUCLEUS-ACCUMBENS AND STRIATUM
EFFECTS OF IBOGA ALKALOIDS ON MORPHINE AND COCAINE SELF-ADMINISTRATION IN RATS - RELATIONSHIP TO TREMORIGENIC EFFECTS AND TO EFFECTS ON DOPAMINE RELEASE IN NUCLEUS-ACCUMBENS AND STRIATUM
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DOI：
10.1016/0006-8993(94)90948-2
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发表时间：
1994-09-19
期刊：
影响因子：
2.9
通讯作者：
CARLSON, JN
中科院分区：
文献类型：
--
作者：
GLICK, SD;KUEHNE, ME;CARLSON, JN
伊博加因是一种自然产生的生物碱，已被认为能有效治疗阿片类药物和兴奋剂成瘾，并据报道可减少大鼠对吗啡和可卡因的自我给药。本研究试图确定其他iboga生物碱以及化学上相关的骆驼蓬生物碱是否也会减少大鼠静脉注射吗啡和可卡因的次数。由于ibogaine和harmarine都能引起震颤，这一效应可能与小脑蠕虫的神经毒性有关，因此对其他iboga生物碱的催眠活性进行了评估。最后，鉴于多巴胺能中脑边缘系统参与药物滥用的作用，本研究确定了部分牛膝生物碱对伏核和纹状体多巴胺及其代谢物胞外水平的影响。所有受试生物碱(即伊波甘碱、丹参碱、R和S冠花碱、R和S冠花碱、去乙基冠花碱和骆驼蓬碱)均可剂量依赖性地减少吗啡和可卡因的摄入量(2.580 mg/kg)；在服用部分(但不是全部)这些生物碱(即伊波甘碱、丹参碱、去乙基冠状花青碱和冠状花青碱的R-异构体)后的第二天，吗啡和可卡因的摄入量也明显减少。在一些大鼠中，在单次注射或每周两到三次注射其中一种或另一种生物碱后，吗啡或可卡因的摄入量持续减少几天；R-ibogamine产生的这种效果比其他任何生物碱都更稳定。在用来评估给药效果的剂量下，伊波甘碱、丹参碱、去乙基冠花碱和骆驼蓬碱均可诱发震颤至少2-3h；冠花碱和伊波甘胺的两种对映体均可引起非常微弱的无震颤。采用在体微透析法，比较冠桂胺和伊博胺的R-和S对映体对伏隔核和纹状体细胞外多巴胺水平的影响。R-对映体降低了两个脑区的多巴胺水平，而S对映体在这两个区域的多巴胺水平没有显着变化。这项研究的结果表明，牛膝生物碱的抗成瘾和促颤栗作用是可以分离的，这些生物碱对药物自我给药的长期影响似乎与特定脑区多巴胺能活动的初始下降有关。
Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids. At the doses used to assess effects on drug self-administration, ibogaine, tabernanthine, desethylcoronaridine and harmaline all induced tremors for at least 2-3 h; both enantioners of both coronaridine and ibogamine induced very weak no tremors. Using in vivo microdialysis, the effects of the R- and S-enantiomers of coronaridine and ibogamine on extracellular dopamine levels in the nucleus accumbaens and striatum were compared. The R-entantiomers decreased dopamine levels in both brain regions whereas the S-enantiomers produced no significant changes in dopamine levels in either region. The results of this study indicate that the 'anti-addictive' and tremorigenic effects of the iboga alkaloids can be dissociated and that long-term effects of these alkaloids on drug self-administration appear to be related to initial decreases in dopaminergic activity in specific brain areas.