大鼠裸盖菇素和5-MeO-DMT鉴别线索的药理学特征及其在鉴定新型致幻剂中的翻译价值。

IF 5.5 3区 医学 Q1 CLINICAL NEUROLOGY
Guy A Higgins, Cam MacMillan, Ines de Lannoy, Carolyn Tyler, Malik Slassi
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引用次数: 0

摘要

背景与目的:药物鉴别程序为裸盖菇素、麦角酸二乙胺(LSD)、N,N-二甲基色胺(DMT)和5-甲氧基-N,N-二甲基色胺(5-MeO-DMT)等致幻剂的临床前研究做出了重要贡献。其中最重要的是强调了中枢5-HT2A受体激动剂作为致幻活性介质的关键作用,其次,在啮齿动物中完全推广到5-HT2A受体激动剂的药物识别,可能会在人类中引起致幻活性,显示出正向翻译价值。然而,关于与幻觉相关的临床暴露如何反向转化为大鼠的概括概况的信息相对较少。方法:本系列实验采用两组雄性Sprague-Dawley大鼠,一组接受裸盖菇素(0.5 mg/kg SC)提示,另一组接受5-MeO-DMT (1 mg/kg SC)提示。结果:替代和拮抗试验分别支持5-HT2A和5-HT1A受体在每种线索的介导中的主要作用。裸盖菇素的血浆暴露(5-52 ng/mL)与临床暴露与人类感知效应相关重叠。对于DMT和LSD,与人类相比,大鼠需要更高的暴露量。使用每种迷幻药的大约ED90剂量的时程研究显示,在药物水平推广的持续时间方面,LSD > psilocybin > 5-MeO-DMT大于或等于DMT的时间分布不同,与临床经验表现出良好的一致性。除LSD外,血浆暴露与药物水平普遍化之间存在良好的时间相关性。在LSD中发现的这种脱节也反映在诊所的类似发现中。结论:综上所述,本研究支持并扩展了药物鉴别试验作为一种转化方法在致幻剂临床前研究中的价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics.

Background and aims: Drug discrimination procedures have made important contributions to the pre-clinical investigation of psychedelic drugs, such as psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). One of the most important being to highlight the critical role of central 5-HT2A receptor agonism as a mediator of hallucinogenic activity, and secondly, drugs that fully generalise to a 5-HT2A receptor agonist cued drug discrimination in rodents, may elicit hallucinogenic activity in humans, showing a forward translational value. However, there is relatively little information about how clinical exposures associated with hallucinations back-translate to generalisation profiles in the rat.

Methods: The present series of experiments utilised two cohorts of male Sprague-Dawley rats, one trained to a psilocybin (0.5 mg/kg SC) cue, and the second trained to a 5-MeO-DMT (1 mg/kg SC) cue.

Results: Tests of substitution and antagonism supported the primary role of 5-HT2A and 5-HT1A receptors, respectively, in the mediation of each cue. Plasma exposures of psilocin required for generalisation to the psilocybin cue (5-52 ng/mL) overlapped with clinical exposures associated with perceptual effects in humans. With respect to DMT and LSD, higher exposures were required in the rat compared to humans. Time-course studies using an approximate ED90 dose of each psychedelic showed differing temporal profiles in terms of duration of drug-lever generalisation, with LSD > psilocybin > 5-MeO-DMT ⩾ DMT, showing good agreement with clinical experience. With the exception of LSD, there was a good temporal association between plasma exposure and drug lever generalisation. The disconnect noted for LSD is mirrored by similar findings in the clinic.

Conclusions: In summary, the present studies both support and extend the value of the drug discrimination assay as a translational approach to the pre-clinical study of psychedelic drugs.

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来源期刊
Journal of Psychopharmacology
Journal of Psychopharmacology 医学-精神病学
CiteScore
8.60
自引率
4.90%
发文量
126
审稿时长
3-8 weeks
期刊介绍: The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.
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