Partial MHC/Neuroantigen Peptide Constructs: A Potential Neuroimmune-Based Treatment for Methamphetamine Addiction

Relapse rates following current methamphetamine abuse treatments are very high (∼40–60%), and the neuropsychiatric impairments (e.g., cognitive deficits, mood disorders) that arise and persist during remission from methamphetamine addiction likely contribute to these high relapse rates. Pharmacotherapeutic development of medications to treat addiction has focused on neurotransmitter systems with only limited success, and there are no Food and Drug Administration approved pharmacotherapies for methamphetamine addiction. A growing literature shows that methamphetamine alters peripheral and central immune functions and that immune factors such as cytokines, chemokines, and adhesion molecules play a role in the development and persistence of methamphetamine induced neuronal injury and neuropsychiatric impairments. The objective of this study was to evaluate the efficacy of a new immunotherapy, partial MHC/neuroantigen peptide construct (RTL551; pI-Ab/mMOG-35-55), in treating learning and memory impairments induced by repeated methamphetamine exposure. C57BL/6J mice were exposed to two different methamphetamine treatment regimens (using repeated doses of 4 mg/kg or 10 mg/kg, s.c.). Cognitive performance was assessed using the Morris water maze and CNS cytokine levels were measured by multiplex assay. Immunotherapy with RTL551 improved the memory impairments induced by repeated methamphetamine exposure in both mouse models of chronic methamphetamine addiction. Treatment with RTL551 also attenuated the methamphetamine induced increases in hypothalamic interleukin-2 (IL-2) levels. Collectively, these initial results indicate that neuroimmune targeted therapies, and specifically RTL551, may have potential as treatments for methamphetamine-induced neuropsychiatric impairments.当前甲基苯丙胺（methamphetamine）成瘾治疗后的复发率极高（约40%~60%），而甲基苯丙胺成瘾者戒断期间出现并持续存在的神经精神障碍（如认知缺陷、心境障碍）很可能是这类高复发率的诱因。目前针对成瘾治疗药物的研发多聚焦于神经递质系统，但收效甚微，且美国食品药品监督管理局（Food and Drug Administration, FDA）尚未批准任何用于甲基苯丙胺成瘾的药物治疗方案。越来越多的研究表明，甲基苯丙胺会改变外周与中枢免疫功能，细胞因子、趋化因子、黏附分子等免疫因子在甲基苯丙胺诱导的神经元损伤及神经精神障碍的发生与持续过程中发挥作用。本研究旨在评估一种新型免疫疗法——部分主要组织相容性复合体（major histocompatibility complex, MHC）/神经抗原肽构建物（RTL551; pI-Ab/mMOG-35-55）——对反复甲基苯丙胺暴露诱导的学习记忆障碍的治疗效果。实验采用C57BL/6J小鼠，设置两种不同的甲基苯丙胺给药方案：皮下注射重复给予4mg/kg或10mg/kg剂量。通过莫里斯水迷宫（Morris water maze）评估小鼠认知表现，采用多重检测法测定中枢神经系统细胞因子水平。结果显示，RTL551免疫疗法可改善两种慢性甲基苯丙胺成瘾小鼠模型中反复甲基苯丙胺暴露诱导的记忆障碍；同时，RTL551治疗还可缓解甲基苯丙胺诱导的下丘脑白细胞介素-2（interleukin-2, IL-2）水平升高。综上，这些初步结果表明，靶向神经免疫的疗法，尤其是RTL551，有望用于治疗甲基苯丙胺诱导的神经精神障碍。