Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABAA Receptors to Histamine Receptor 3 Antagonists
Increased Sensitivity of Mice Lacking Extrasynaptic δ-Containing GABAA Receptors to Histamine Receptor 3 Antagonists
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DOI：
10.3389/fphar.2020.00594
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发表时间：
2020-05-06
影响因子：
5.6
通讯作者：
Panula, Pertti
中科院分区：
文献类型：
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作者：
Abdurakhmanova, Shamsiiat;Grotell, Milo;Panula, Pertti
下丘脑后部的组胺/γ-氨基丁酸（GABA）神经元向许多脑区发送广泛的投射，并参与稳定清醒状态。最近的研究表明，从组胺/GABA神经元释放的GABA作用于突触外GABA（A）受体并平衡组胺的兴奋作用。在目前的研究中，我们发现囊泡GABA转运蛋白mRNA的存在下丘脑组胺能神经元，这表明囊泡释放GABA的大多数量化。由于组胺/GABA神经元很少形成常规突触，因此从这些神经元释放的GABA可能通过体积传递扩散到靶区域并作用于突触外GABA受体。为了研究这一假设，使用缺乏突触外GABA（A）受体δ亚基（Gabrd KO）的小鼠。采用药理学方法激活组胺/GABA神经元并诱导组胺和可能的GABA释放。对照和Gabrd KO小鼠用组胺受体3（Hrh 3）反向激动剂ciproxifan和pitolisant处理，其阻断组胺/GABA神经元上的Hrh 3自身受体并且组胺依赖性地促进觉醒。低剂量的环丙昔芬（1 mg/kg）和pitolisant（5 mg/kg）减少了Gabrd KO小鼠的运动，但在WT小鼠中没有。EEG记录显示，Gabrd KO小鼠也比对照小鼠对环丙昔芬（3 mg/kg）的促醒作用更敏感。与WT组相比，Gabrd KO小鼠中与NREM睡眠相关的低频δ波被显著抑制。组胺合成抑制剂α-氟甲基组氨酸（α FMH）可阻断环丙沙星诱导的觉醒。这些结果表明，组胺/GABA神经元释放的组胺和GABA都参与了脑唤醒状态的调节，含有δ亚基的GABA（A）受体参与介导GABA反应。
Histamine/gamma-aminobutyric acid (GABA) neurons of posterior hypothalamus send wide projections to many brain areas and participate in stabilizing the wake state. Recent research has suggested that GABA released from the histamine/GABA neurons acts on extrasynaptic GABA(A) receptors and balances the excitatory effect of histamine. In the current study, we show the presence of vesicular GABA transporter mRNA in a majority of quantified hypothalamic histaminergic neurons, which suggest vesicular release of GABA. As histamine/GABA neurons form conventional synapses infrequently, it is possible that GABA released from these neurons diffuses to target areas by volume transmission and acts on extrasynaptic GABA receptors. To investigate this hypothesis, mice lacking extrasynaptic GABA(A) receptor delta subunit (Gabrd KO) were used. A pharmacological approach was employed to activate histamine/GABA neurons and induce histamine and presumably, GABA, release. Control and Gabrd KO mice were treated with histamine receptor 3 (Hrh3) inverse agonists ciproxifan and pitolisant, which block Hrh3 autoreceptors on histamine/GABA neurons and histamine-dependently promote wakefulness. Low doses of ciproxifan (1 mg/kg) and pitolisant (5 mg/kg) reduced locomotion in Gabrd KO, but not in WT mice. EEG recording showed that Gabrd KO mice were also more sensitive to the wake-promoting effect of ciproxifan (3 mg/kg) than control mice. Low frequency delta waves, associated with NREM sleep, were significantly suppressed in Gabrd KO mice compared with the WT group. Ciproxifan-induced wakefulness was blocked by histamine synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH). The findings indicate that both histamine and GABA, released from histamine/GABA neurons, are involved in regulation of brain arousal states and delta-containing subunit GABA(A) receptors are involved in mediating GABA response.