Agonist properties of N,N-Dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors
Agonist properties of N,N-Dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors
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DOI：
10.1016/s0091-3057(98)00110-5
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发表时间：
1998-11-01
影响因子：
3.6
通讯作者：
Sanders-Bush, E
中科院分区：
文献类型：
--
作者：
Smith, RL;Canton, H;Sanders-Bush, E
广泛的行为和生化证据表明，在致幻药物的作用机制中，5-HT 2A受体（可能还有5-HT 2C受体）具有激动剂作用。然而，已发表的致幻色胺类似物N，N-二甲基色胺（DMT）的体外药理学性质与这一假设不一致。因此，我们对DMT在5-HT 2A和5-HT 2C受体上的性质进行了广泛的研究。在用5-HT 2A受体或5-HT 2C受体转染的成纤维细胞中，DMT激活主要的细胞内信号传导途径（磷酸肌醇水解），其程度与5-羟色胺产生的程度相当。由于药物功效随受体密度和细胞微环境而变化，因此我们还使用行为和生物化学方法研究了天然制剂中DMT的性质。训练大鼠在双杠杆选择范例中区分拮抗剂酮色林和激动剂1-（2，5-二甲氧基-4-碘苯基）-2-氨基丙烷（DOI）。药理学研究表明，对DOI和酮色林的反应反映了对5-HT_（2A）受体的激动剂和拮抗剂活性，因此是评价DMT体内功能特性的合适模型。完整的脉络丛用于评价内源性5-HT 2C受体的激动剂特性;在该天然制剂中，DMT是5-HT 2C受体的部分激动剂。因此，我们得出结论，DMT在5-HT 2A和5-HT 2A受体上都表现为激动剂。一个明显的差异在于5-HT 2C而不是5-HT 2A受体随时间对DMT表现出深刻的脱敏。这种差异是有趣的，根据最近的报告，DMT的致幻活性在人类中不耐受，并表明5-HT 2C受体在DMT的作用中起着不太突出的作用。(C)1998年爱思唯尔科学公司
Extensive behavioral and biochemical evidence suggests an agonist role at the 5-HT2A receptor, and perhaps the 5-HT2C receptor, in the mechanism of action of hallucinogenic drugs. However the published in vitro pharmacological properties of N,N-dimethyltryptamine (DMT), an hallucinogenic tryptamine analog, are not consistent with this hypothesis. We, therefore, undertook an extensive investigation into the properties of DMT at 5-HT2A and 5-HT2C receptors. In fibroblasts transfected with the 5-HT2A receptor or the 5-HT2C receptor, DMT activated the major intracellular signaling pathway (phosphoinositide hydrolysis) to an extent comparable to that produced by serotonin. Because drug efficacy changes with receptor density and cellular microenvironment, we also examined the properties of DMT in native preparations using a behavioral and biochemical approach. Rats were trained to discriminate an antagonist ketanserin from an agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in a two-lever choice paradigm. Pharmacological studies showed that responding on the DOI and ketanserin lever reflected agonist and antagonist activity at 5-HT2A receptors, and hence, was a suitable model for evaluating the in vivo functional properties of DMT, Like other 5-HT2A receptor agonists, DMT substituted fully for DOI. Intact choroid plexus was used to evaluate the agonist properties at endogenous 5-HT2C receptors; DMT was a partial agonist at 5-HT2C receptors in this native preparation. Thus, we conclude that DMT behaves as an agonist at both 5-HT2A and 5-HT2A receptors. One difference was evident in that the 5-HT2C, but not the 5-HT2A, receptor showed a profound desensitization to DMT over time. This difference is interesting in light of the recent report that the hallucinogenic activity of DMT does not tolerate in humans and suggests the 5-HT2C receptor plays a less prominent role in the action of DMT. (C) 1998 Elsevier Science Inc.