The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Young-Jung Kim, Wun-A Kook, Shi-Xun Ma, Bo-Ram Lee, Yong-Hyun Ko, Seon-Kyung Kim, Youyoung Lee, Jae-Gyeong Lee, Sooyeun Lee, Kyeong-Man Kim, Seok-Yong Lee, Choon-Gon Jang
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引用次数: 0

Abstract

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Abstract Image

Abstract Image

新型精神活性物质 25E-NBOMe 通过多巴胺 D1 受体信号传导诱导雄性啮齿动物的奖赏相关行为
新型精神活性物质(NPS)是一种旨在规避物质监管政策的新型精神药物。25E-NBOMe (2-(4-乙基-2,5-二甲氧基苯基)-N-(2-甲氧基苄基)乙胺)最近被确认为一种 NPS,据报道,其娱乐性滥用正在迅速增加。然而,25E-NBOMe 的精神药理作用和机制尚未得到研究。我们利用雄性小鼠的条件性位置偏好和雄性大鼠的自我给药范例研究了 25E-NBOMe 的滥用潜力。此外,我们还使用了免疫印迹分析法、酶联免疫吸附分析法和微透析法来确定 25E-NBOMe 在纳氏核(NAc)中的分子效应。我们的数据表明,25E-NBOMe能诱导条件性位置偏好,而NAc中的多巴胺能信号传导介导了这些作用。给予25E-NBOMe后,雄性小鼠NAc中多巴胺转运体和多巴胺D1受体(D1DR)的表达增强,雄性小鼠和大鼠NAc中的多巴胺水平降低。在雄性小鼠的 NAc 中,还观察到细胞内多巴胺能通路、DARPP32 和 CREB 磷酸化的诱导。值得注意的是,药理阻断 D1DR 或化学抑制 NAc 中表达 D1DR 的中刺神经元可减轻雄性小鼠的 25E-NBOMe 诱导的条件性位置偏好。我们还利用雄性小鼠头部抽搐反应试验研究了 25E-NBOMe 的致幻特性,发现这种行为是由血清素 2A 受体活性介导的。我们的研究结果表明,D1DR 信号传导可能控制着 25E-NBOMe 的致瘾潜力。此外,我们的研究还为了解药物使用障碍的潜在机制和改进受管制药物的管理提供了新的视角。
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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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