An Animal Model For Chronic Methamphetamine Toxicity

人类受试者长期滥用甲基苯丙胺与神经毒性有关，在行为上表现为认知缺陷。用正电子发射断层扫描(PET)和[F-18]脱氧葡萄糖测定了甲基苯丙胺自身给药对4只3~5岁未用药恒河猴基础脑代谢的影响。在基线PET研究之前，受试者接受了按照固定比率(FR)30时间表对食物做出反应的训练。然后，这些猴子被训练给自己注射甲基苯丙胺(0.025毫克/公斤/注射)，按FR 10时间表进行。第二次PET FDG扫描是在甲基苯丙胺训练期结束时进行的，持续30-82天，在此期间，猴子总共接受了40.9-104.9毫克/公斤的甲基苯丙胺。在第二次PET扫描时，这些猴子至少有24小时没有服用甲基苯丙胺。PET研究的图像通过将区域值除以全球计数来归一化。使用联合配准图像上包含28个区域的ROI模板，我们发现在给予甲基苯丙胺后，左右额叶皮质和左侧丘脑的新陈代谢显著增加。我们的结果表明，在人类甲基苯丙胺滥用者的皮质区域观察到的较高的葡萄糖代谢正常率可能是他们吸毒史的结果，而不是由于吸毒前的特征差异。开始在大鼠身上进行研究，以建立一个模型，在该模型中可以测试毒性的时程、效果的可逆性和治疗方式的潜在效果。老鼠接受了一种慢性治疗方案，该方案旨在模仿人类甲基苯丙胺滥用者自我给药的方式。用2-脱氧-D-[1-[C-14]葡萄糖(DG)方法评估脑功能的影响，该方法提供了大脑局部葡萄糖代谢率(RCMRglc)的定量地图，rCMRglc是大脑功能的指标。与对照组动物相比，慢性甲基苯丙胺在34个区域中的14个区域和整个大脑中产生了较低的rCMRglc。最强烈的影响出现在脾后皮质、尾壳核头、丘脑腹后核和伏核核心。慢性服用甲基苯丙胺的大鼠基础脑代谢降低可能反映了长期使用该药物的毒性效应。甲基苯丙胺在大鼠大脑中代谢作用的广泛分布表明，滥用这种药物的人有广泛的大脑缺陷，这是他们认知和情感症状的基础。

Chronic methamphetamine abuse in human subjects is associated with neuronal toxicity, expressed behaviorally as cognitive deficits. Positron emission tomography (PET) and [F-18]fluorodeoxyglucose were used to determine the effects of methamphetamine self-administration on basal cerebral metabolism in four drug-naive Rhesus monkeys (3-5 y.o.). Prior to the baseline PET study, the subjects were trained to respond for food on a fixed ratio (FR) 30 schedule. The monkeys were then trained to self-administer methamphetamine (0.025 mg/kg/injection) on an FR 10 schedule. A second PET FDG scan was acquired at the end of the methamphetamine training period, which lasted 30-82 days during which the monkeys received a total of 40.9 - 104.9 mg/kg of methamphetamine. At the time of the second PET scan, the monkeys had not self-administered methamphetamine for at least 24 h. The images from the PET studies were normalized by dividing the regional values by global counts. Using an ROI template with 28 regions on co-registered images, we found significantly increased metabolism after methamphetamine administration in right and left frontal cortices and left thalamus. Our results suggest that the higher normalized rates of glucose metabolism observed in cortical areas of human methamphetamine abusers could be a consequence of their history of drug abuse rather than due to predrug trait differences. Studies in rats were initiated to establish a model in which the time course to toxicity, reversibility of effects and potential effects of treatment modalities could be tested. Rats were subjected to a chronic treatment regimen that was designed to mimic the manner in which human methamphetamine abusers self-administer the drug. The effects of brain function were assessed using the 2-deoxy-D-[1-[C-14]]glucose (DG) method, which provides quantitative maps of regional cerebral metabolic rates for glucose (rCMRglc), an index of brain function. Compared to effects in control animals, chronic methamphetamine produced lower rCMRglc in 14 out of 34 regions assayed and in whole brain. The most robust effects occurred in the retrosplenial cortex, head of the caudate putamen, ventroposterior thalamic n. and core of the nucleus accumbens. Lower basal brain metabolism in rats receiving chronic methamphetamine may reflect the toxic effects of chronic use of this drug. The wide distribution of the metabolic effects of methamphetamine in the rat brain suggests that human abusers of this drug have extensive cerebral deficits that underlie their cognitive and emotional symptoms.