Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons
Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons
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DOI：
10.1111/j.1469-7793.2001.0731e.x
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发表时间：
2001-05-01
影响因子：
5.5
通讯作者：
Hsu, KS
中科院分区：
文献类型：
--
作者：
Huang, CC;Lo, SW;Hsu, KS
1.纹状体是大麻素（CB）运动效应的关键作用部位。然而，纹状体神经元上CB受体激活的电生理后果尚未建立。在此，我们首次报道了大麻模拟物氨基烷基吲哚WIN 55，212 -2和内源性大麻素anandamide在脑切片制备中显著抑制皮质纹状体神经元对纹状体神经元的突触传递。选择性CB 1受体拮抗剂SR 141716可有效地逆转这种抑制作用. WIN 55，212 -2显著增加突触诱发的EPSC的成对脉冲易化，而对突触后神经元对α-氨基-3-羟基-5-甲基异恶唑-4-丙酸的敏感性没有影响。WIN 55，212 -2还降低了自发的、动作电位依赖性EPSC（sEPSC）的频率，而不改变其振幅分布。WIN 55，212 -2的灌流引起膜超极化，伴随着输入电阻的降低。这两种作用都被细胞内铯所阻断。相反，细胞内铯不能影响WIN 55，212 -2介导的突触抑制。G（i/o）蛋白抑制剂百日咳毒素（PTX）可阻断WIN 55，212 -2介导的突触抑制作用，但GABA（A）受体拮抗剂荷包牡丹碱或GABA（B）受体拮抗剂SCH 50911.5不能阻断WIN 55，212 -2介导的突触抑制作用。用N型Ca 2+通道拮抗剂ω-芋螺毒素GVIA预处理选择性地消除了WIN-55，212 -2介导的突触抑制。这些结果表明;大麻素通过激活突触前CB 1受体抑制N-型Ca 2+通道活性，进而减少谷氨酸释放，从而抑制皮质纹状体谷氨酸能突触传递。大麻素的突触前作用由PTX敏感的G（i/o）蛋白偶联信号通路介导。
1. The striatum is a crucial site of action for the motor effects of cannabinoids (CBs). However, the electrophysiological consequences of activation of CB receptors on the striatal neurons have not been established. Here we report fur the first time that the cannabimimetic aminoalkylindole WIN 55,212-2 and the endogenous cannabinoid anandamide substantially depress corticostriatal glutamatergic synaptic transmission onto striatal neurons in the brain slice preparation. The selective CB1 receptor antagonist SR 141716 effectively reversed this inhibition.2. WIN 55,212-2 significantly increased the paired-pulse facilitation of synaptically evoked EPSCs, while having no effect on the sensitivity of postsynaptic neurons to alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic acid. WIN 55,212-2 also reduced the frequency of spontaneous, action potential-dependent EPSCs (sEPSCs) without altering their amplitude distribution.3. Superfusion of WIN 55,212-2 elicited a membrane hyperpolarization accompanied by a decrease in input resistance. Both effects were blocked by intracellular caesium. In contrast, intracellular caesium failed to affect WIN 55,212-2-mediated synaptic inhibition.4. The WIN 55,212-2-mediated synaptic inhibition was blocked by the G(i/o) protein inhibitor pertussis toxin (PTX), but not by the GABA(A) receptor antagonist bicuculline or GABA(B) receptor antagonist SCH 50911.5. Pretreatment with the N-type Ca2+ channel antagonist omega -conotoxin GVIA selectively abolished the WIN-55,212-2-mediated synaptic inhibition.6. These results suggest that; cannabinoids depress the corticostriatal glutamatergic synaptic transmission through the activation of presynaptic CB1 receptors to inhibit N-type Ca2+ channel activity, which in turn reduces glutamate release. The presynaptic action of cannabinoids is mediated by a PTX-sensitive G(i/o) protein-coupled signalling pathway.