Belcher Annabelle M, Feinstein Erin M, O'Dell Steven J, Marshall John F
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA.
Neuropsychopharmacology. 2008 May;33(6):1453-63. doi: 10.1038/sj.npp.1301510. Epub 2007 Jul 18.
Methamphetamine (mAMPH) is an addictive drug that produces memory and recall impairments in humans. Animals subjected to a binge mAMPH dosing regimen that damages brain dopamine and serotonin terminals show impairments in an object recognition (OR) task. Earlier research demonstrated that preceding a single-day mAMPH binge regimen with several days of increasing mAMPH doses greatly attenuates its neurotoxicity in rats. The escalating dose (ED) paradigm appears to mimic the human pattern of escalating drug intake. The current aim was to test whether an ED plus binge mAMPH regimen produces OR impairments. In addition to its translational value, this experiment helps address whether monoaminergic neurotoxicity accounts for OR impairments seen after mAMPH administration. To further address this issue, a separate experiment investigated both OR impairments and monoamine transporter integrity in groups of rats treated with a range of mAMPH doses during a single day. An ED mAMPH regimen attenuated the acute hyperthermic response to the subsequent mAMPH binge and prevented the OR impairments and reductions in [125 I]RTI-55 binding to monoamine transporters in striatum, hippocampus (HC), and perirhinal cortex (pRh) that otherwise occur 1 week after the mAMPH binge. Single-day mAMPH regimens (4 x 1mg/kg to 4 x 4 mg/kg, s.c.) dose-dependently produced acute hyperthermia and, 1 week post-mAMPH, produced dose-dependent impairments in OR and reductions in monoamine transporter binding. The OR impairments of single-day mAMPH-treated rats correlated with monoaminergic transporter loss in ventral caudate-putamen, HC, and pRh. In aggregate, these findings suggest a correspondence between mAMPH-induced monoaminergic injury and the resulting OR deficits.
甲基苯丙胺（mAMPH）是一种成瘾性药物，会导致人类出现记忆和回忆障碍。接受损害脑多巴胺和5-羟色胺终末的甲基苯丙胺暴饮给药方案的动物，在物体识别（OR）任务中表现出障碍。早期研究表明，在单日甲基苯丙胺暴饮方案之前给予几天递增剂量的甲基苯丙胺，可大大减轻其对大鼠的神经毒性。递增剂量（ED）模式似乎模仿了人类药物摄入量递增的模式。当前的目的是测试ED加甲基苯丙胺暴饮方案是否会导致OR障碍。除了其转化价值外，该实验还有助于解决单胺能神经毒性是否是甲基苯丙胺给药后出现的OR障碍的原因。为了进一步解决这个问题，一项单独的实验研究了在一天内接受一系列甲基苯丙胺剂量治疗的大鼠组中的OR障碍和单胺转运体完整性。ED甲基苯丙胺方案减弱了对随后甲基苯丙胺暴饮的急性体温过高反应，并预防了在甲基苯丙胺暴饮1周后否则会出现的OR障碍以及纹状体、海马体（HC）和鼻周皮质（pRh）中[125I]RTI-55与单胺转运体结合的减少。单日甲基苯丙胺方案（4×1mg/kg至4×4mg/kg，皮下注射）剂量依赖性地产生急性体温过高，并且在甲基苯丙胺给药后1周，产生剂量依赖性的OR障碍和单胺转运体结合减少。单日甲基苯丙胺治疗的大鼠的OR障碍与腹侧尾状核-壳核、HC和pRh中的单胺能转运体丧失相关。总体而言，这些发现表明甲基苯丙胺诱导的单胺能损伤与由此产生的OR缺陷之间存在对应关系。
