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急性和间断给药以及间断 14 天治疗后戒断后 DBA/2J 小鼠中 4-CMC 和 4-MeO-PVP 的行为效应。

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment.

机构信息

Department of Pharmacodynamics, Medical University of Lodz, 90-151, Lodz, Poland.

出版信息

Neurotox Res. 2021 Jun;39(3):575-587. doi: 10.1007/s12640-021-00329-x. Epub 2021 Jan 11.

Abstract

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

摘要

合成卡西酮作为新型精神活性物质于 21 世纪初出现在市场上,并在药物滥用者中广泛流行。卡西酮通过增强大脑中的多巴胺能、去甲肾上腺素能和 5-羟色胺能神经传递而产生精神兴奋和共情效应,那些能够强有力且选择性地增强多巴胺能传递的物质被认为具有更高的滥用潜力。本研究在 DBA/2J 小鼠中检查了与精神兴奋特性、滥用潜力和成瘾相关的行为效应,研究对象为两种作用于单胺系统的卡西酮,即 4-氯甲卡西酮(4-CMC)和 4-甲氧基-吡咯烷苯丙酮(4-MeO-PVP)。4-CMC 和 4-MeO-PVP 在急性治疗后增加自发运动活动,并在 7 天间歇性治疗后产生行为敏化,这是滥用药物的常见特征。4-MeO-PVP 而不是 4-CMC 在 4 天后产生条件性位置偏好,表明其具有奖赏特性。最后,通过一系列用于评估小鼠抑郁行为标志物的测试来评估 4-CMC 和 4-MeO-PVP 在停止 14 天治疗后诱导戒断症状的能力:悬尾测试、强迫游泳测试、测量绝望和蔗糖偏好测试,测量快感缺失。这三个测试都没有显示出抑郁症状的增加。此外,在接受测试化合物 14 天治疗后,自发运动活动或旋转棒上的运动表现均未受损。这些结果表明,4-CMC 和 4-MeO-PVP 对小鼠进行 14 天治疗后,停药后不会引起明显的戒断症状,也不会导致多巴胺能回路的显著损伤,从而导致运动障碍。本研究表明,4-CMC 和 4-MeO-PVP 在小鼠中产生与滥用相关的行为变化,在更具多巴胺选择性的 4-MeO-PVP 后更为明显。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bf3/8096775/9947bed9d84e/12640_2021_329_Fig1_HTML.jpg

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