Assessment of pharmacological effects and abuse potential of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 in mice.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2024-10-15 DOI:10.1007/s00213-024-06703-9

Kaixi Li, Deli Xu, Yanling Qiao, Lixin Kuai, Xuwen Luo, Bin Di, Peng Xu

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引用次数: 0

Abstract

Rationale: The newly emerging synthetic cannabinoids (SCs) 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201 have been observed to produce effects by activating cannabinoid type 1 (CB1) receptors. Nevertheless, the pharmacological effects and potential for abuse of these three substances remain to be studied. These substances have yet to be regulated in many countries.

Objectives: We investigated the safety, pharmacological effects, rewarding effects, and cannabinoid withdrawal of 5F-EDMB-PICA, CUMYL-PEGACLONE, and NM-2201.

Methods: This study evaluated the drug safety and the cannabinoid-specific pharmacological effects of the three substances through acute toxicity experiments (in which the LD₅₀ of each substance was obtained) and tetrad experiments (comprising assessments of hypothermia, analgesia, locomotion inhibition, and catalepsy). Furthermore, the conditioned place preference (CPP) experiments and withdrawal experiments were conducted to evaluate the rewarding effect and cannabinoid withdrawal potential of the substances in question.

Results: The results demonstrated that all three drugs exhibited certain acute toxic effects and could potentially induce tetrad effects. The data were analyzed using non-linear regression, and the corresponding ED₅₀ values and 95% confidence intervals (CI) were obtained. The rank order of potency was determined to be CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201. In the CPP experiments, it was demonstrated that 5F-EDMB-PICA significantly induced an increase in CPP score at a dose of 0.3 mg/kg, while NM-2201 caused an increase in CPP score and a significant aversion effect at a dose of 2 and 3 mg/kg, respectively. It is noteworthy that all three types of SCs were observed to produce a significant biphasic effect, indicating that CPP scores were biphasic for all compounds. Following the administration of the CB1 receptor antagonist rimonabant, a notable increase in head twitches and paw tremors was observed, indicating that these three SCs induce cannabinoid withdrawal through the mediation of CB1 receptors.

Conclusions: The results of this study indicated that these SCs possess cannabinoid-specific pharmacological effects and abuse potential, which provides substantial experimental data to support the future regulation of these substances.

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评估 5F-EDMB-PICA、CUMYL-PEGACLONE 和 NM-2201 对小鼠的药理作用和滥用潜力。

理由：据观察，新出现的合成大麻素（SC）5F-EDMB-PICA、CUMYL-PEGACLONE 和 NM-2201 可通过激活大麻素 1 型（CB1）受体产生作用。不过，这三种物质的药理作用和滥用潜力仍有待研究。许多国家尚未对这些物质进行监管：我们研究了 5F-EDMB-PICA、CUMYL-PEGACLONE 和 NM-2201 的安全性、药理作用、奖励效应和大麻素戒断作用：本研究通过急性毒性实验（获得每种物质的半数致死剂量）和四分体实验（包括低体温、镇痛、运动抑制和催眠评估）评估了这三种物质的药物安全性和大麻素特异性药理作用。此外，还进行了条件性位置偏好（CPP）实验和戒断实验，以评估相关物质的奖赏效应和大麻素戒断潜能：结果表明，这三种药物都有一定的急性毒性作用，并可能诱发四联效应。使用非线性回归分析了数据，并得出了相应的 ED50 值和 95% 的置信区间 (CI)。药效排序为：CUMYL-PEGACLONE > 5F-EDMB-PICA > NM-2201。在 CPP 实验中，5F-EDMB-PICA 在 0.3 毫克/千克的剂量下可显著提高 CPP 评分，而 NM-2201 在 2 毫克/千克和 3 毫克/千克的剂量下可分别提高 CPP 评分和产生显著的厌恶效应。值得注意的是，观察到所有三种 SC 都产生了显著的双相效应，表明所有化合物的 CPP 评分都是双相的。给药 CB1 受体拮抗剂利莫那班后，观察到头部抽搐和爪震明显增加，表明这三种 SC 通过 CB1 受体的介导诱导大麻素戒断：本研究的结果表明，这些 SCs 具有大麻素特异性药理作用和滥用潜力，为今后对这些物质的监管提供了大量实验数据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.