Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions.
Mefloquine effects on ventral tegmental area dopamine and GABA neuron inhibition: a physiologic role for connexin-36 GAP junctions.
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DOI：
10.1002/syn.20907
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发表时间：
2011-08
期刊：
影响因子：
2.3
通讯作者：
Steffensen, Scott C.
中科院分区：
文献类型：
--
作者：
Allison, David W.;Wilcox, Rebecca S.;Ellefsen, Kyle L.;Askew, Caitlin E.;Hansen, David M.;Wilcox, Jeffrey D.;Sandoval, Stephanie S.;Eggett, Dennis L.;Yanagawa, Yuchio;Steffensen, Scott C.
缝隙连接蛋白36（Cx36）参与GABA中间神经元的同步化过程。我们以前已经确定了Cx36连接的腹侧被盖区（VTA）GABA神经元的人口，可能会调节中脑边缘多巴胺（DA）神经传递，涉及奖励的自然行为和滥用药物的系统。本研究的目的是确定甲氟喹（MFQ）对小鼠中脑DA和GABA神经元抑制的影响，以及Cx36 GJs在调节小鼠中脑VTA DA神经元活性中的作用。在青少年野生型（WT）小鼠的脑切片中，Cx36选择性GJ阻断剂甲氟喹（MFQ，25 μM）使腹侧被盖区DA神经元sIPSC频率增加6倍，mIPSC频率增加3倍。然而，在Cx36 KO小鼠中，MFQ仅使sIPSC和mIPSC频率增加三倍。非选择性GJ阻断剂甘珀酸（CBX，100 μM）使WT小鼠的DA神经元sIPSC频率增加两倍，不影响Cx36 KO小鼠的sIPSC，也不影响WT或Cx36 KO小鼠的mIPSC。有趣的是，MFQ对VTA GABA神经元sIPSC频率没有影响。我们还研究了MFQ对WT和Cx36 KO小鼠腹侧被盖区DA神经元放电率和电流诱发的尖峰的影响，发现MFQ降低了WT DA神经元放电率和电流诱发的尖峰，但在Cx36 KO小鼠中没有改变这些措施。综上所述，这些发现表明阻断Cx36 GJs增加VTA DA神经元抑制，并且GJs在调节VTA DA神经元抑制中起关键作用。
Connexin-36 (Cx36) gap junctions (GJs) appear to be involved in the synchronization of GABA interneurons in many brain areas. We have previously identified a population of Cx36-connected ventral tegmental area (VTA) GABA neurons that may regulate mesolimbic dopamine (DA) neurotransmission, a system implicated in reward from both natural behaviors and drugs of abuse. The aim of this study was to determine the effect mefloquine (MFQ) has on midbrain DA and GABA neuron inhibition, and the role Cx36 GJs play in regulating midbrain VTA DA neuron activity in mice. In brain slices from adolescent wild-type (WT) mice the Cx36-selective GJ blocker mefloquine (MFQ, 25 μM) increased VTA DA neuron sIPSC frequency sixfold, and mIPSC frequency threefold. However, in Cx36 KO mice, MFQ only increased sIPSC and mIPSC frequency threefold. The nonselective GJ blocker carbenoxolone (CBX, 100 μM) increased DA neuron sIPSC frequency twofold in WT mice, did not affect Cx36 KO mouse sIPSCs, and did not affect mIPSCs in WT or Cx36 KO mice. Interestingly, MFQ had no effect on VTA GABA neuron sIPSC frequency. We also examined MFQ effects on VTA DA neuron firing rate and current-evoked spiking in WT and Cx36 KO mice, and found that MFQ decreased WT DA neuron firing rate and current-evoked spiking, but did not alter these measures in Cx36 KO mice. Taken together these findings suggest that blocking Cx36 GJs increases VTA DA neuron inhibition, and that GJs play in key role in regulating inhibition of VTA DA neurons.
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影响因子：
4.9
作者：
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通讯作者：
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影响因子：
56.9
作者：
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DOI：
10.1073/pnas.0402044101
发表时间：
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影响因子：
11.1
作者：
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影响因子：
16.2
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