GHB depresses fast excitatory and inhibitory synaptic transmission via GABAB receptors in mouse neocortical neurons
GHB depresses fast excitatory and inhibitory synaptic transmission via GABAB receptors in mouse neocortical neurons
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DOI：
10.1093/cercor/11.5.424
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发表时间：
2001-05-01
期刊：
影响因子：
3.7
通讯作者：
Mody, I
中科院分区：
文献类型：
--
作者：
Jensen, K;Mody, I
γ-羟基丁酸（GHB）是一种滥用药物，可引起镇静和欣快。然而，过量可能会严重降低意识水平，或者可能是致命的，特别是当与其他物质结合时。研究表明，GHB效应是通过对丘脑皮层通路和局部新皮层回路的作用介导的，尽管GHB在单个新皮层神经元水平上的效应尚不清楚。采用鲸细胞膜片钳技术，研究了GHB对12 ~ 33日龄小鼠脑片新皮层神经元的作用。我们发现GHB抑制由突触前动作电位放电驱动的GABA能和谷氨酸能自发抑制性和兴奋性突触后电流（IPSC和EPSC）的频率和幅度，而不依赖于Ca 2+进入的微型IPSC的幅度和频率不受影响。使用最小的刺激，GHB降低了在抑制性突触释放到新皮质层2/3锥体细胞的可能性。此外，GHB直接超极化层2/3非锥体细胞高达11 mV，并抑制动作电位放电。GHB的上述作用均通过GABA（B）受体介导。总之，GH B激活参与快速突触传递的新皮层神经元中的突触前和突触后GABA（B）受体，导致新皮层网络活动的强烈抑制。我们认为，GABA（B）受体拮抗剂可用于治疗急性GHB中毒。
Gamma-hydroxybutyrate (GHB) is a drug of abuse which induces sedation and euphoria. However, overdoses can severely depress the level of consciousness or can be fatal especially when combined with other substances. Studies have suggested that the GHB-effects are mediated via actions on thalamocortical pathways and local neocortical circuits, although the effect of GHB at the level of single neocortical neurons is not clear. Using whale-cell patch-clamp recordings, we studied the effects of GHB on neocortical neurons in brain slices from 12- to 33-day-old mice. We found that GHB depressed the frequency and amplitude of GABAergic and glutamatergic spontaneous inhibitory and excitatory post-synaptic currents (IPSCs and EPSCs) driven by presynaptic action potential firing, while the amplitude and frequency of Ca2+ entry-independent miniature IPSCs were not affected. Using minimal stimulation, GHB reduced the probability of release at inhibitory synapses onto neocortical layer 2/3 pyramidal cells. Also, GHB directly hyperpolarized layer 2/3 non-pyramidal cells by up to 11 mV and inhibited action potential firing. All these effects of GHB were mediated via GABA(B)-receptors. In conclusion, GHB activates both pre- and postsynaptic GABA(B)-receptors in neocortical neurons participating in fast synaptic transmission, leading to a powerful depression of neocortical network activity. We propose that GABA(B)-receptor antagonists may be useful in the treatment of acute GHB intoxication.