Methamphetamine Regulation of Firing Activity of Dopamine Neurons
Methamphetamine Regulation of Firing Activity of Dopamine Neurons
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DOI：
10.1523/jneurosci.1392-16.2016
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发表时间：
2016-10-05
影响因子：
5.3
通讯作者：
Khoshbouei, Habibeh
中科院分区：
文献类型：
--
作者：
Lin, Min;Sambo, Danielle;Khoshbouei, Habibeh
甲基苯丙胺（METH）是多巴胺转运蛋白的底物，通过与多巴胺摄取竞争和增加多巴胺通过转运蛋白的反向转运来增加细胞外多巴胺水平。METH也被证明可以改变多巴胺神经元的兴奋性。METH调节多巴胺神经元内在放电行为的机制还不太清楚。因此，我们确定了一个意想不到的和独特的属性METH的调节小鼠多巴胺神经元的放电活动。METH产生了一个短暂的增强自发的棘波活动的中脑多巴胺神经元，随后由自发的棘波活动的逐步减少。动作电位形态学检查显示，METH增加了半宽度，并产生较大的变异系数的峰间期，表明METH暴露影响这些神经元的电压依赖性钾通道的活动。由于METH已被证明影响Ca2+稳态，METH扩大动作电位并降低后超极化幅度的意外发现使我们想知道METH是否改变了Ca2+激活钾（BK）通道的活性。首先，我们通过它们的电压依赖性和它们对BK通道阻断剂或开放剂的反应来识别多巴胺神经元中的BK通道。虽然METH抑制BK通道介导的单一电流的幅度，BK通道开放剂NS 1619衰减METH对动作电位增宽，后超极化抑制和自发性锋电位活动减少的影响。活细胞全内反射荧光显微镜，电生理学，和生化分析extrastMETH曝光降低BK通道的活性，降低BK亚基水平在质膜。
Methamphetamine (METH) is a substrate for the dopamine transporter that increases extracellular dopamine levels by competing with dopamine uptake and increasing reverse transport of dopamine via the transporter. METHhas also been shown to alter the excitability of dopamine neurons. The mechanism ofMETHregulation of the intrinsic firing behaviors of dopamine neurons is less understood. Herewe identified an unexpected and unique property ofMETHon the regulation of firing activity of mouse dopamine neurons. METHproduced a transient augmentation of spontaneous spike activity of midbrain dopamine neurons that was followed by a progressive reduction of spontaneous spike activity. Inspection of action potential morphology revealed thatMETHincreased the half-width and produced larger coefficients of variation of the interspike interval, suggesting that METH exposure affected the activity of voltage-dependent potassium channels in these neurons. Since METH has been shown to affect Ca2+ homeostasis, the unexpected findings that METH broadened the action potential and decreased the amplitude of afterhyperpolarization led us to ask whether METH alters the activity of Ca2+-activated potassium (BK) channels. First, we identified BK channels in dopamine neurons by their voltage dependence and their response to a BK channel blocker or opener. While METH suppressed the amplitude of BK channel-mediated unitary currents, the BK channel opener NS1619 attenuated the effects of METH on action potential broadening, afterhyperpolarization repression, and spontaneous spike activity reduction. Live-cell total internal reflection fluorescence microscopy, electrophysiology, and biochemical analysis suggestMETH exposure decreased the activity of BK channels by decreasing BK-subunit levels at the plasma membrane.