Herring Nicole R, Schaefer Tori L, Gudelsky Gary A, Vorhees Charles V, Williams Michael T
Division of Neurology (MLC 7044), Cincinnati Children's Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Psychopharmacology (Berl). 2008 Sep;199(4):637-50. doi: 10.1007/s00213-008-1183-y. Epub 2008 May 29.
Methamphetamine (MA) has been implicated in cognitive deficits in humans after chronic use. Animal models of neurotoxic MA exposure reveal persistent damage to monoaminergic systems but few associated cognitive effects.
Since questions have been raised about the typical neurotoxic dosing regimen used in animals and whether it adequately models human cumulative drug exposure, these experiments examined two different dosing regimens.
Rats were treated with one of the two regimens: one based on the typical neurotoxic regimen (4 x 10 mg/kg every 2 h) and one based on pharmacokinetic modeling (Cho AK, Melega WP, Kuczenski R, Segal DS Synapse 39:161-166, 2001) designed to better represent accumulating plasma concentrations of MA as seen in human users (24 x 1.67 mg/kg once every 15 min) matched for total daily dose. In two separate experiments, dosing regimens were compared for their effects on markers of neurotoxicity or on behavior.
On markers of neurotoxicity, MA showed decreased dopamine (DA) and 5-HT, increased glial fibrillary acidic protein, and increased corticosterone levels regardless of dosing regimen 3 days post-treatment. Behaviorally, MA-treated groups, regardless of dosing regimen, showed hypoactivity, increased initial hyperactivity to a subsequent MA challenge, impaired novel object recognition, impaired learning in a multiple T water maze test of path integration, and no differences on spatial navigation or reference memory in the Morris water maze. After behavioral testing, reductions of DA and 5-HT remained.
MA treatment induces an effect on path integration learning not previously reported. Dosing regimen had no differential effects on behavior or neurotoxicity.
长期使用甲基苯丙胺（MA）与人类认知缺陷有关。神经毒性MA暴露的动物模型显示单胺能系统持续受损，但相关的认知影响较少。
由于有人对动物中使用的典型神经毒性给药方案以及它是否能充分模拟人类累积药物暴露提出了疑问，因此这些实验研究了两种不同的给药方案。
大鼠接受两种给药方案之一的治疗：一种基于典型的神经毒性方案（每2小时4×10mg/kg），另一种基于药代动力学模型（Cho AK、Melega WP、Kuczenski R、Segal DS，《突触》39:161 - 166，2001），设计该方案是为了更好地反映人类使用者中MA血浆浓度的累积情况（每15分钟24×1.67mg/kg），两种方案的每日总剂量相同。在两个独立的实验中，比较了给药方案对神经毒性标志物或行为的影响。
在神经毒性标志物方面，无论给药方案如何，治疗后3天，MA均显示多巴胺（DA）和5 - 羟色胺（5 - HT）减少、胶质纤维酸性蛋白增加以及皮质酮水平升高。行为学上，无论给药方案如何，MA治疗组均表现出活动减少、对后续MA刺激的初始多动增加、新物体识别受损、在路径整合的多重T水迷宫测试中学习受损，并且在莫里斯水迷宫的空间导航或参考记忆方面没有差异。行为测试后，DA和5 - HT仍然减少。
MA治疗对路径整合学习产生了一种以前未报道过的影响。给药方案对行为或神经毒性没有差异影响。
