Sekine Yoshimoto, Ouchi Yasuomi, Sugihara Genichi, Takei Nori, Yoshikawa Etsuji, Nakamura Kazuhiko, Iwata Yasuhide, Tsuchiya Kenji J, Suda Shiro, Suzuki Katsuaki, Kawai Masayoshi, Takebayashi Kiyokazu, Yamamoto Shigeyuki, Matsuzaki Hideo, Ueki Takatoshi, Mori Norio, Gold Mark S, Cadet Jean L
Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.
J Neurosci. 2008 May 28;28(22):5756-61. doi: 10.1523/JNEUROSCI.1179-08.2008.
Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, (11)C-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ((11)C-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of (11)C-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of (11)C-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.
甲基苯丙胺是一种广为人知的成瘾性药物，其使用与多种神经精神不良事件相关，且对大脑的多巴胺能和5-羟色胺能系统有毒性。甲基苯丙胺诱发的神经病理学与小胶质细胞表达增加有关，小胶质细胞被认为参与大脑中的促毒性或保护机制。尽管在甲基苯丙胺神经毒性的动物模型中已观察到反应性小胶质细胞增生，但尚无研究报道人类甲基苯丙胺滥用者中小胶质细胞激活的状态。本研究报告了12名戒断甲基苯丙胺的滥用者和12名年龄、性别及教育程度相匹配的对照受试者，他们使用一种用于激活小胶质细胞的放射性示踪剂(11)C-(1-[2-氯苯基]-N-甲基-N-[1-甲基丙基]-3-异喹啉甲酰胺)((11)C-PK11195)进行了正电子发射断层扫描。采用房室分析来估计(11)C-PK11195在具有多巴胺能和/或5-羟色胺能神经支配的脑区中的结合电位定量水平。在所有脑区中，甲基苯丙胺滥用者的(11)C-PK11195结合平均水平均高于对照受试者(高出>250%；所有p<0.01)。此外，中脑、纹状体、丘脑以及眶额皮质和岛叶皮质中的结合水平(p<0.05)与甲基苯丙胺戒断持续时间呈负相关。这些结果表明，长期自我服用甲基苯丙胺可导致人类甲基苯丙胺滥用者大脑中出现反应性小胶质细胞增生，这种激活水平似乎会在更长时间的戒断后消退。
