Guy A Higgins, Cam MacMillan, Ines de Lannoy, Carolyn Tyler, Malik Slassi
{"title":"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。","authors":"Guy A Higgins, Cam MacMillan, Ines de Lannoy, Carolyn Tyler, Malik Slassi","doi":"10.1177/02698811251361453","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251361453"},"PeriodicalIF":5.5000,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacological characterisation of psilocybin and 5-MeO-DMT discriminative cues in the rat and their translational value for identifying novel psychedelics.\",\"authors\":\"Guy A Higgins, Cam MacMillan, Ines de Lannoy, Carolyn Tyler, Malik Slassi\",\"doi\":\"10.1177/02698811251361453\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":16892,\"journal\":{\"name\":\"Journal of Psychopharmacology\",\"volume\":\" \",\"pages\":\"2698811251361453\"},\"PeriodicalIF\":5.5000,\"publicationDate\":\"2025-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/02698811251361453\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/02698811251361453","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.