An Animal Model For Chronic Methamphetamine Toxicity

慢性甲基苯丙胺滥用与神经毒性有关，表现为认知缺陷。采用正电子发射断层扫描（PET）和[F-18]氟脱氧葡萄糖测定甲基安非他命自我给药对4只无药恒河猴（3-5岁）基础脑代谢的影响。在基线PET研究之前，受试者接受训练，按照固定比例（FR） 30的时间表对食物做出反应。然后，这些猴子被训练成按照fr10时间表自行服用甲基苯丙胺（0.025 mg/kg/注射）。在为期30-82天的甲基苯丙胺训练结束时进行第二次PET FDG扫描，在此期间，猴子接受了40.9 - 104.9 mg/kg的甲基苯丙胺。在第二次PET扫描时，猴子至少24小时没有自行服用甲基苯丙胺。PET研究的图像通过将区域值除以全局计数进行标准化。利用共配图像上28个区域的ROI模板，我们发现甲基苯丙胺给药后左右额叶皮层和左丘脑的代谢显著增加。我们的研究结果表明，在人类甲基苯丙胺滥用者的皮质区域观察到的更高的正常葡萄糖代谢率可能是他们的药物滥用史的结果，而不是由于药物前的性状差异。在大鼠身上进行研究，以建立模型，测试其毒性的时间过程、作用的可逆性和治疗方式的潜在效应。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。使用2-脱氧-d -[1-[C-14]]葡萄糖（DG）方法评估脑功能的影响，该方法提供了区域脑葡萄糖代谢率（rCMRglc）的定量图，这是脑功能的指标。与对照动物相比，慢性甲基苯丙胺在34个分析区域中的14个区域和全脑产生较低的rCMRglc。最强烈的影响发生在脾后皮质、尾状壳核头部、丘脑腹后核和伏隔核核心。长期服用甲基苯丙胺的大鼠较低的基础脑代谢可能反映了长期使用这种药物的毒性作用。甲基苯丙胺在大鼠大脑中广泛分布的代谢效应表明，这种药物的人类滥用者有广泛的大脑缺陷，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.