Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Synapse. 2013 Aug;67(8):476-88. doi: 10.1002/syn.21654. Epub 2013 Mar 19.
The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.5 weeks. Escalating METH exposure was delivered by dynamic infusion (DI) that incorporated a "humanized" plasma METH half life or by intravenous self-administration (IVSA) that included binge intakes. Kinetic modeling of DI and IVSA for 24 h periods during the final week of METH exposure showed that plasma METH levels remained between 0.7 and 1.5 µM. Animals were sacrificed during their last METH administration for autoradiography assessment using [³H]ligands and D2 agonist-induced [³⁵S]GTPγS binding. DA transporter binding was decreased (DI, 34%; IVSA, 15%) while vesicular monoamine transporter binding and substantia nigra DA cell numbers were unchanged. Decreases were measured for D2 receptor (DI and IVSA, 15-20%) and [³⁵S]GTPγS binding (DI, 35%; IVSA, 18%). These similar patterns of DI and IVSA associated decreases in striatal DA markers reflect consequences of cumulative METH exposure and not the drug delivery method. For METH IVSA, individual differences were observed, yet each animal's total intake was similar within and across three 24-h binges. IVSA rodent models may be useful for identifying molecular mechanisms that are associated with METH binges in humans.
甲基苯丙胺（METH）滥用的持续蔓延刺激了旨在了解其长期暴露后果的研究。在长期 METH 停药后，实验研究已经描述了黑质纹状体多巴胺（DA）系统参数的改变，但在 METH 暴露期间进行类似评估的研究较少。在这里，我们报告了非条件和条件 METH 给药 7.5 周后大鼠 METH 血浆药代动力学和纹状体 DA 系统改变。通过动态输注（DI）进行递增的 METH 暴露，该方法整合了“人性化”的血浆 METH 半衰期，或通过静脉内自我给药（IVSA），包括狂欢性摄入。在 METH 暴露的最后一周的 24 小时期间，对 DI 和 IVSA 的动力学建模显示，血浆 METH 水平保持在 0.7 到 1.5µM 之间。在最后一次 METH 给药期间，动物被处死，用于使用 [³H]配体进行放射自显影评估和 D2 激动剂诱导的 [³⁵S]GTPγS 结合。DA 转运体结合减少（DI，34%；IVSA，15%），而囊泡单胺转运体结合和黑质 DA 细胞数量不变。D2 受体（DI 和 IVSA，15-20%）和 [³⁵S]GTPγS 结合（DI，35%；IVSA，18%）也降低了。这些与 DI 和 IVSA 相关的纹状体 DA 标志物的类似减少模式反映了累积 METH 暴露的后果，而不是药物输送方法。对于 METH IVSA，观察到个体差异，但每个动物在三个 24 小时狂欢期间的总摄入量在内部和之间都是相似的。IVSA 啮齿动物模型可能有助于确定与人类 METH 狂欢相关的分子机制。
