Propofol facilitates glutamatergic transmission to neurons of the ventrolateral preoptic nucleus.
Propofol facilitates glutamatergic transmission to neurons of the ventrolateral preoptic nucleus.
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DOI：
10.1097/aln.0b013e3181bf1d79
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发表时间：
2009-12
期刊：
影响因子：
8.8
通讯作者：
Ye JH
中科院分区：
文献类型：
--
作者：
Li KY;Guan YZ;Krnjević K;Ye JH
有大量证据表明，麻醉的镇静成分是通过下丘脑神经元上的γ-氨基丁酸A受体介导的，该受体负责觉醒，特别是在结节乳头核。这些γ-氨基丁酸A受体是腹外侧视前区GABA能神经元的靶标：当这些神经元变得活跃时，它们会抑制产生觉醒的核团并诱导睡眠。根据最近的研究，异丙酚通过增强VLPO诱导的突触抑制，使靶细胞对γ-氨基丁酸A更敏感来诱导镇静。我们探索了异丙酚通过促进兴奋性输入到VLPO GABA能神经元而不是直接促进镇静的可能性。从VLPO细胞记录到自发的兴奋性突触后电流--主要是机械分离的，但也在大鼠的脑片中记录到。在分离的VLPO GABA能神经元上，异丙酚增加谷氨酸能自发兴奋性突触后电流的频率，但不影响其平均幅度。异丙酚的作用分别被γ-氨基丁酸A型受体的特异性激动剂和拮抗剂加巴嗪阻断。−共转运体介导的Na+-K+-Cl−内向转运的阻断剂布美他尼也能抑制这种作用。在脑片上，异丙酚还增加了自发兴奋性突触后电流的频率，并在低剂量时加速了VLPO细胞的放电。异丙酚的镇静作用至少部分是通过增加腹外侧视前区GABA能神经元的放电，间接地通过激活谷氨酸能传入的γ-氨基丁酸A型受体：由于这些轴突/终末具有相对较高的内部Cl-−浓度，它们被GABA能药物如异丙酚去极化，从而促进谷氨酸的释放。
There is much evidence that the sedative component of anesthesia is mediated by γ-aminobutyric acid A receptors on hypothalamic neurons responsible for arousal, notably in the tuberomammillary nucleus. These γ-aminobutyric acid A receptors are targeted by GABAergic neurons in the ventrolateral preoptic area (VLPO): when these neurons become active, they inhibit the arousal-producing nuclei and induce sleep. According to recent studies, propofol induces sedation by enhancing VLPO-induced synaptic inhibition, making the target cells more responsive to γ-aminobutyric acid A. We explored the possibility that propofol also promotes sedation less directly by facilitating excitatory inputs to the VLPO GABAergic neurons. Spontaneous excitatory postsynaptic currents were recorded from VLPO cells – principally mechanically isolated, but also in slices from rats. In isolated VLPO GABAergic neurons, propofol increased the frequency of glutamatergic spontaneous excitatory postsynaptic currents without affecting their mean amplitude. Propofol’s action was mimicked by muscimol and prevented by gabazine, respectively a specific agonist and antagonist at γ-aminobutyric acid type-A receptors. It was also suppressed by bumetanide, a blocker of Na+-K+-Cl− cotransporter-mediated inward Cl− transport. In slices, propofol also increased the frequency of spontaneous excitatory postsynaptic currents and, at low doses, accelerated firing of VLPO cells. Propofol induces sedation, at least in part, by increasing firing of GABAergic neurons in ventrolateral preoptic area, indirectly by activation of γ-aminobutyric acid type-A receptors on glutamatergic afferents: because these axons/terminals have a relatively high internal Cl− concentration, they are depolarized by GABAergic agents such as propofol which thus enhance glutamate release.