Antagonism of α3β4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration
Antagonism of α3β4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration
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DOI：
10.1016/s0014-2999(02)01284-0
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发表时间：
2002-03-01
影响因子：
5
通讯作者：
Fleck, MW
中科院分区：
文献类型：
--
作者：
Glick, SD;Maisonneuve, IM;Fleck, MW
iboga生物碱ibobalidine和新iboga生物碱同系物18-甲氧基冠孢定是推定的抗成瘾剂。采用膜片钳技术，测定了伊波替尼和18-甲氧基冠孢定对各种神经递质受体离子通道亚型的作用。伊波替尼和18-甲氧基冠孢定都是α 3 β 4烟碱受体的拮抗剂，两种药物在该部位的作用均强于α 4 β 2烟碱受体或NMDA或5-HT 3受体; 18-甲氧基冠孢定在这方面的选择性高于伊波替尼。在吗啡和甲基苯丙胺自我给药的研究中，评估了18-甲氧基可乐定与美加明或美沙芬以及美加明与美沙芬的低剂量组合的作用。美加明和美沙芬也被证明是α 3 β 4烟碱受体的拮抗剂。所有三种药物组合都减少了吗啡和甲基苯丙胺的自我给药，如果单独给药，这些剂量是无效的。这些数据与α 3 β 4受体的拮抗作用是调节药物寻求行为的潜在机制的假设一致。18-甲氧冠孢定显然具有更大的选择性，该网站比其他药物，并可能是第一个通过这种新的机制，以产生广谱的抗成瘾活性的一个新的合成剂类。(C)2002 Elsevier Science B. V.保留所有权利。
The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha3beta4 nicotinic receptors and both agents were more potent at this site than at alpha4beta2 nicotinic receptors or at NMDA or 5-HT3 receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha3beta4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha3beta4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity. (C) 2002 Elsevier Science B.V. All rights reserved.