Gervasi Nicolas, Monnier Zohreh, Vincent Pierre, Paupardin-Tritsch Daniele, Hughes Stuart W, Crunelli Vincenzo, Leresche Nathalie
Neurobiologie des Processus Adaptatifs, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 7102-Université Pierre et Marie Curie, F-75005 Paris, France.
J Neurosci. 2003 Dec 10;23(36):11469-78. doi: 10.1523/JNEUROSCI.23-36-11469.2003.
The systemic injection of gamma-hydroxybutyric acid (GHB) elicits spike and wave discharges (SWDs), the EEG hallmark of absence seizures, and represents a well established, widely used pharmacological model of this nonconvulsive epilepsy. Despite this experimental use of GHB, as well as its therapeutic use in narcolepsy and its increasing abuse, however, the precise cellular mechanisms underlying the different pharmacological actions of this drug are still unclear. Because sensory thalamic nuclei play a key role in the generation of SWDs and sleep rhythms, and because direct injection of GHB in the ventrobasal (VB) thalamus elicits SWDs, we investigated GHB effects on corticothalamic EPSCs and GABAergic IPSCs in VB thalamocortical (TC) neurons. GHB (250 microm-10 mm) reversibly decreased the amplitude of electrically evoked EPSCs and GABAA IPSCs via activation of GABAB receptors; however, approximately 60% of the IPSCs were insensitive to low (250 microm-1.0 mm) GHB concentrations. The putative GHB receptor antagonist NSC 382 applied alone had a number of unspecific effects, whereas it either had no action on, or further increased, the GHB-elicited effects on synaptic currents. Low GHB concentrations (250 microm) were also effective in increasing absence-like intrathalamic oscillations evoked by cortical afferent stimulation. These results indicate that low concentrations of GHB, similar to the brain concentrations that evoke SWDs in vivo, differentially affect excitatory and inhibitory synaptic currents in TC neurons and promote absence-like intrathalamic oscillations. Furthermore, the present data strengthen previous suggestions on the GHB mechanism of sleep promotion and will help focus future studies on the cellular mechanisms underlying its abuse.
γ-羟基丁酸（GHB）的全身注射会引发棘波和慢波放电（SWDs），这是失神发作的脑电图特征，并且代表了这种非惊厥性癫痫的一种成熟且广泛使用的药理学模型。然而，尽管GHB有这种实验用途，以及其在发作性睡病中的治疗用途和日益增加的滥用情况，但这种药物不同药理作用背后的确切细胞机制仍不清楚。由于感觉丘脑核在SWDs和睡眠节律的产生中起关键作用，并且由于在腹侧基底（VB）丘脑直接注射GHB会引发SWDs，我们研究了GHB对VB丘脑皮质（TC）神经元中皮质丘脑兴奋性突触后电流（EPSCs）和γ-氨基丁酸能抑制性突触后电流（IPSCs）的影响。GHB（250微摩尔 - 10毫摩尔）通过激活GABAB受体可逆地降低电诱发的EPSCs和GABAA IPSCs的幅度；然而，大约60%的IPSCs对低浓度（250微摩尔 - 1.0毫摩尔）的GHB不敏感。单独应用的假定GHB受体拮抗剂NSC 382有许多非特异性作用，而它对GHB引起的突触电流效应要么没有作用，要么进一步增强。低浓度的GHB（250微摩尔）在增加由皮质传入刺激诱发的类失神丘脑内振荡方面也有效。这些结果表明，低浓度的GHB，类似于在体内引发SWDs的脑内浓度，对TC神经元中的兴奋性和抑制性突触电流有不同影响，并促进类失神丘脑内振荡。此外，目前的数据强化了先前关于GHB促进睡眠机制的观点，并将有助于聚焦未来关于其滥用背后细胞机制的研究。
