Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
J Pharmacol Exp Ther. 2012 Feb;340(2):295-303. doi: 10.1124/jpet.111.188433. Epub 2011 Oct 27.
Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.
临床前研究表明，反复给予甲基苯丙胺（METH）注射（此处称为“狂欢”治疗）会导致多巴胺能持续减少。一些研究还检查了大鼠中 METH 自我给药的持续神经化学影响，但结果各不相同。这些后续研究很重要，因为：1）它们与 METH 滥用的研究有关；2）非条件 METH 治疗的效果不一定预测条件暴露的效果。因此，本研究调查了 METH 自我给药对多巴胺能神经元功能的影响。结果表明，根据一种方案进行 METH 自我给药，可产生与人类 METH 滥用者死后报告的大脑 METH 水平相当的水平（0.06 mg/ 输注；8 小时/ 7 天），可降低纹状体多巴胺转运蛋白（DAT）摄取和/或免疫反应性，在最后一次自我给药后 8 或 30 天进行评估。增加每次输注的 METH 剂量不会加剧这些缺陷。这些缺陷的严重程度与影像学研究中报告的停用 METH 滥用者 DAT 密度降低相似。值得注意的是，METH 自我给药减轻了随后的狂欢 METH 暴露引起的多巴胺能神经元功能持续减少以及神经胶质纤维酸性蛋白免疫反应性增加。这种保护独立于 METH 药代动力学的改变，但可能归因于（至少部分归因于）预处理诱导的狂欢诱导性体温升高的衰减。综上所述，这些结果可能为人类 METH 滥用者报告的神经化学缺陷提供了一些见解。
