Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents
Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents
复制标题
DOI：
10.1152/jn.00094.2012
复制
发表时间：
2012-08-01
影响因子：
2.5
通讯作者：
Beckstead, Michael J.
中科院分区：
文献类型：
--
作者：
Branch, Sarah Y.;Beckstead, Michael J.
分支SY，Beckstead MJ。甲基苯丙胺对多巴胺神经元兴奋性和多巴胺介导的突触电流产生双向的浓度依赖性作用。J Neurophysiol 108：802-809，2012.首次发表于2012年5月16日; doi：10.1152/jn.00094.2012.-安非他明类化合物通常用于增强认知和治疗注意力缺陷/多动症，但它们也起阳性兴奋剂的作用，并且以远远超过临床相关性的剂量自我给药。许多这些化合物（包括甲基苯丙胺）是多巴胺再摄取转运蛋白的底物，通过抑制摄取和促进反向转运来提高细胞外多巴胺。这产生细胞外多巴胺的增加，其通过自身受体激活抑制多巴胺神经元放电，并因此使阶段性多巴胺神经传递（一种重要的学习信号）钝化。然而，这些机制并不能解释在临床有用浓度下观察到的有益行为效应。在本研究中，我们使用膜片钳电生理学在小鼠中脑切片显示，令人惊讶的是，低浓度的甲基苯丙胺实际上增强多巴胺神经传递，并通过多巴胺转运蛋白介导的兴奋性电导增加多巴胺神经元放电。这两种效应都被高浓度的甲基苯丙胺逆转，甲基苯丙胺通过多巴胺D2自身受体激活抑制放电，并降低多巴胺介导的突触电流的峰值振幅。这些竞争，浓度依赖性的影响，甲基苯丙胺表明一种机制的相互作用，较低浓度的甲基苯丙胺可以克服自身受体介导的抑制在索马，以增加相位多巴胺传输。
Branch SY, Beckstead MJ. Methamphetamine produces bidirectional, concentration-dependent effects on dopamine neuron excitability and dopamine-mediated synaptic currents. J Neurophysiol 108: 802-809, 2012. First published May 16, 2012; doi:10.1152/jn.00094.2012.-Amphetamine-like compounds are commonly used to enhance cognition and to treat attention deficit/hyperactivity disorder, but they also function as positive reinforcers and are self-administered at doses far exceeding clinical relevance. Many of these compounds (including methamphetamine) are substrates for dopamine reuptake transporters, elevating extracellular dopamine by inhibiting uptake and promoting reverse transport. This produces an increase in extracellular dopamine that inhibits dopamine neuron firing through autoreceptor activation and consequently blunts phasic dopamine neurotransmission, an important learning signal. However, these mechanisms do not explain the beneficial behavioral effects observed at clinically useful concentrations. In the present study, we have used patch-clamp electrophysiology in slices of mouse midbrain to show that, surprisingly, low concentrations of methamphetamine actually enhance dopamine neurotransmission and increase dopamine neuron firing through a dopamine transporter-mediated excitatory conductance. Both of these effects are reversed by higher concentrations of methamphetamine, which inhibit firing through dopamine D2 autoreceptor activation and decrease the peak amplitude of dopamine-mediated synaptic currents. These competing, concentration-dependent effects of methamphetamine suggest a mechanistic interplay by which lower concentrations of methamphetamine can overcome autoreceptor-mediated inhibition at the soma to increase phasic dopamine transmission.