Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands.
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom 73170, Thailand.
Neurotoxicology. 2023 Dec;99:305-312. doi: 10.1016/j.neuro.2023.11.006. Epub 2023 Nov 17.
Methamphetamine (METH) is a psychostimulant with a very high addiction rate. Prolonged use of METH has been observed as one of the root causes of neurotoxicity. Melatonin (Mel) has been found to have a significant role in METH-induced neurotoxicity. This study aimed to investigate the restorative effect of Mel on behavioral flexibility in METH-induced cognitive deficits. Male Sprague-Dawley rats were randomly assigned to be intraperitoneally injected with saline (control) or Meth at 5 mg/kg for 7 consecutive days. Then, METH injection was withdrawn and rats in each group were subcutaneously injected with saline or Mel at 10 mg/kg for 14 consecutive days. The stereotypic behavioral test and attentional set-shifting task (ASST) were used to evaluate neurological functions and cognitive flexibility, respectively. Rats developed abnormal features of stereotyped behaviors and deficits in cognitive flexibility after 7 days of METH administration. However, post-treatment with Mel for 14 days after METH withdrawal dramatically ameliorated the neurological and cognitive deficits in METH-treated rats. Blood biomarkers indicated METH-induced systemic low-grade inflammation. Moreover, METH-induced endoplasmic reticulum (ER) stress in the prefrontal cortex was diminished by melatonin supplementation. These findings might reveal the therapeutic potential of Mel in METH toxicity-induced neurological and cognitive deficits.
甲基苯丙胺（METH）是一种具有很高成瘾性的精神兴奋剂。长期使用 METH 被认为是神经毒性的根本原因之一。褪黑素（Mel）已被发现在 METH 诱导的神经毒性中具有重要作用。本研究旨在探讨 Mel 对 METH 诱导的认知功能障碍中行为灵活性的恢复作用。雄性 Sprague-Dawley 大鼠随机分为腹腔注射生理盐水（对照组）或 METH（5mg/kg）连续 7 天。然后，停止 METH 注射，每组大鼠连续 14 天皮下注射生理盐水或 Mel（10mg/kg）。刻板行为测试和注意定势转换任务（ASST）分别用于评估神经功能和认知灵活性。METH 给药 7 天后，大鼠出现刻板行为异常特征和认知灵活性缺陷。然而，METH 停药后用 Mel 治疗 14 天可显著改善 METH 处理大鼠的神经和认知缺陷。血液生物标志物表明 METH 诱导全身低度炎症。此外，褪黑素补充剂可减轻前额叶皮质中 METH 诱导的内质网（ER）应激。这些发现可能揭示了 Mel 在 METH 毒性诱导的神经和认知缺陷中的治疗潜力。
