Meth math: modeling temperature responses to methamphetamine
Meth math: modeling temperature responses to methamphetamine
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DOI：
10.1152/ajpregu.00365.2013
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发表时间：
2014-04-01
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影响因子：
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通讯作者：
Zaretsky, Dmitry V.
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文献类型：
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作者：
Molkov, Yaroslav I.;Zaretskaia, Maria V.;Zaretsky, Dmitry V.
Molkov YI，Zaretskaia MV，Zaretsky DV.冰毒数学：模拟温度对冰毒的反应。Am J Physiol Regul Integr Comp Physiol 306：R552-R566，2014。首次出版于2014年2月5日; doi：10.1152/ajpregu. 00365.2013.-甲基苯丙胺（Methe）可引起极端体温过高，这与实验室动物和人类的神经毒性和死亡有关。本研究的目的是揭示一个复杂的剂量依赖性的温度反应的机制，以甲基的神经元回路的数学建模。在前人研究的基础上，我们构建了一个以兴奋性、髓质和交感节前神经元（SPN）为核心的神经网络。甲基直接刺激兴奋性节点，抑制性驱动器针对髓结，并且在高剂量下，额外的兴奋性驱动器影响SPN节点。所有的模型参数（连接，灵敏度和时间常数的重量）进行拟合实验时间序列的温度响应1，3，5，和10毫克/公斤甲基。建模表明，最低剂量的甲基，这引起了立即和短暂的体温过高的温度反应，涉及在髓上水平的神经元兴奋。在中间剂量的甲基后的反应延迟是在髓质水平的神经元抑制的结果。最后，由最高剂量的甲基苯丙胺引起的体温快速而稳健的升高涉及高剂量兴奋性驱动的激活。抑制机制的损伤可引起危及生命的体温升高，并使其成为甲氧苯使用者致命性体温过高的合理原因。我们预计，研究假定的神经元网站的甲基行动和参与该系统的详细模型的神经介质可能会导致更有效的策略，用于预防和治疗安非他明类兴奋剂引起的高热。
Molkov YI, Zaretskaia MV, Zaretsky DV. Meth math: modeling temperature responses to methamphetamine. Am J Physiol Regul Integr Comp Physiol 306: R552-R566, 2014. First published February 5, 2014; doi: 10.1152/ajpregu. 00365.2013.-Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetaminelike stimulants.