Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cagliari, Italy.
National Research Council of Italy, Institute of Translational Pharmacology, UOS of Cagliari, Scientific and Technological Park of Sardinia POLARIS, Pula, Italy.
Neuropharmacology. 2019 Jan;144:219-232. doi: 10.1016/j.neuropharm.2018.10.031. Epub 2018 Oct 23.
Methoxetamine (MXE) is a novel psychoactive substance that can induce several short-term effects on emotional states and behavior. However, little is known about the persistent emotional and behavioral effects of MXE. Moreover, neurotoxic effects of MXE have been hypothesized, but never demonstrated in vivo. To clarify these issues, rats received repeated treatment with MXE every other day (0.1-0.5 mg/kg, i.p., × 5), and 7 days later they were challenged with MXE (0.1-0.5 mg/kg, i.p.). Behavioral effects of MXE were first evaluated by measuring emission of ultrasonic vocalizations and locomotor activity after each administration. Thereafter, persistent behavioral effects of MXE were evaluated, starting 8 days after challenge, through elevated plus maze, spontaneous alternation, novel object recognition, and marble burying tests. After completion of behavioral analysis, neurotoxic effects of MXE were evaluated by measuring densities of dopamine transporter, tyrosine hydroxylase, and serotonin transporter in various brain regions. Repeated treatment and challenge with MXE affected neither calling behavior nor locomotor activity of rats. Conversely, rats previously treated with MXE exhibited behavioral alterations in the elevated plus maze, marble burying and novel object recognition tests, suggestive of increased anxiety and impaired non-spatial memory. Noteworthy, the same rats displayed dopaminergic damage in the medial prefrontal cortex, nucleus accumbens, caudate-putamen, substantia nigra pars compacta, and ventral tegmental area, along with accumbal serotonergic damage. Our findings show for the first time that repeated administration of MXE induces persistent behavioral abnormalities and neurotoxicity in rats, which can help elucidating the risks associated with human MXE consumption.
甲氧基苯己酮（MXE）是一种新型精神活性物质，可对情绪状态和行为产生多种短期影响。然而，人们对 MXE 的持续情绪和行为影响知之甚少。此外，有人假设 MXE 具有神经毒性作用，但尚未在体内得到证实。为了阐明这些问题，大鼠每隔一天接受 MXE 的重复治疗（0.1-0.5mg/kg，腹腔注射，×5），7 天后用 MXE 进行挑战（0.1-0.5mg/kg，腹腔注射）。每次给药后，通过测量超声波发声和运动活动来评估 MXE 的行为效应。此后，从挑战后第 8 天开始，通过高架十字迷宫、自发交替、新物体识别和大理石掩埋测试评估 MXE 的持续行为效应。完成行为分析后，通过测量各种脑区的多巴胺转运体、酪氨酸羟化酶和 5-羟色胺转运体的密度来评估 MXE 的神经毒性作用。重复治疗和 MXE 挑战既不影响大鼠的叫声行为，也不影响其运动活动。相反，先前用 MXE 治疗的大鼠在高架十字迷宫、大理石掩埋和新物体识别测试中表现出行为改变，表明焦虑增加和非空间记忆受损。值得注意的是，相同的大鼠在中前额叶皮层、伏隔核、尾壳核、黑质致密部和腹侧被盖区以及伏隔核中表现出多巴胺能损伤，以及 Accumbal 中 5-羟色胺能损伤。我们的研究结果首次表明，重复给予 MXE 可在大鼠中诱导持续的行为异常和神经毒性，这有助于阐明与人类 MXE 消费相关的风险。
