O'Neil Meghan L, Kuczenski Ronald, Segal David S, Cho Arthur K, Lacan Goran, Melega William P
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, 90095-1735, USA.
Synapse. 2006 Nov;60(6):465-73. doi: 10.1002/syn.20320.
A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.1-4.0 mg/kg over 14 days) attenuated the toxicity of a subsequently administered high-dose METH binge (4 x 6 mg/kg at 2 h interval) that itself produced behavioral stereotypy, increases in core temperature, and decreases in DA system phenotypic markers in caudate-putamen (CP). Using those ED-METH and binge protocols in the present studies, pharmacokinetic and pharmacodynamic parameters that may have contributed to the apparent neuroprotection afforded by ED-METH were assessed. The ED-METH regimen itself reduced [(3)H]WIN35,428 (WIN) binding to the dopamine transporter (DAT) by 15% in CP, but did not affect DA content. During the METH binge, ED-METH pretreated animals showed attenuated increases in core temperature while concurrent microdialysis studies in CP showed a reduced DA response despite unaltered extracellular levels of METH. At 1 h after the binge, concentrations of METH and its metabolite amphetamine in brain and plasma were unaffected by the ED-METH. The results show that ED-METH pretreatment produces reductions in DAT binding and the DA response during a subsequent METH binge by altering pharmacodynamic and not pharmacokinetic parameters.
人类甲基苯丙胺（METH）滥用的一个主要特征是在高剂量暴露之前剂量逐渐增加。剂量递增期（EDs）可能与对METH药理和毒性作用方面的耐受性发展有关，但药代动力学和药效学因素的相对贡献尚未明确界定。在我们之前对大鼠的研究中，我们表明用ED-METH方案（14天内0.1-4.0mg/kg）预处理可减轻随后给予的高剂量METH暴饮（4×6mg/kg，间隔2小时）的毒性，该暴饮本身会产生行为刻板症、核心体温升高以及尾状核-壳核（CP）中多巴胺（DA）系统表型标志物减少。在本研究中使用那些ED-METH和暴饮方案，评估了可能导致ED-METH所提供的明显神经保护作用的药代动力学和药效学参数。ED-METH方案本身使CP中[³H]WIN35,428（WIN）与多巴胺转运体（DAT）的结合减少了15%，但不影响DA含量。在METH暴饮期间，经ED-METH预处理的动物核心体温升高减弱，而同时在CP中进行的微透析研究显示DA反应降低，尽管METH的细胞外水平未改变。在暴饮后1小时，脑和血浆中METH及其代谢物苯丙胺的浓度不受ED-METH的影响。结果表明，ED-METH预处理通过改变药效学而非药代动力学参数，在随后的METH暴饮期间使DAT结合和DA反应降低。
