The Role of GABA and Glutamate Neurons in General Anesthetic Action

全麻状态似乎包括几种成分；例如，无意识，健忘症，不动和抑制反射反应。这种状态可以通过增强抑制性神经传递（如GABA神经元）、抑制兴奋性神经传递（如谷氨酸神经元）或两者结合来实现。在本研究中，研究了增加GABA脑浓度对小鼠麻醉的影响。通过腹腔注射GABA-转氨酶抑制剂gabaculine和GABA摄取抑制剂NO-711来提高脑内GABA浓度。采用两种方法作为不同的终点评估全麻作用；翻正反射（LORR）和捏尾反应的丧失。LORR可能反映了无意识，而捏尾反应的丧失可能反映了麻醉的综合成分。加巴库林剂量依赖性诱导的LORR， ED_<50>值为100 (75-134)mg/kg，但本研究中使用的最高剂量（400 mg/kg）并未导致尾夹效应的丧失。在一项脑微透析研究中，加巴库林（100 mg/kg）显著提高海马细胞外GABA水平（高达3179.0% ^^+__- 314.9%）。高剂量NO-711 （50 mg/kg）诱导了失调，但既不产生LORR，也不产生夹尾反应。NO-711 （50 mg/kg）诱导的细胞外GABA水平仅增加269.7% ^^+__- 24.2%。相反，临床使用的静脉麻醉药异丙酚会导致翻正反射和捏尾反应的丧失。在之前的研究中，我们报道了异丙酚诱导的麻醉至少部分是由GABA和谷氨酸神经元介导的。提示全麻作用可能是由增强抑制性神经传递和抑制兴奋性神经传递共同作用引起的。

General anesthetic state appears to include several components ; e.g., unconsciousness, amnesia, immobility and suppression of reflex responses. The state can be achieved by enhancing inhibitory neurotransmission (e.g., GABA neurons), by inhibiting excitatory neurotransmission (e.g., glutamate neurons) or by a combination of both. In this study, the effects of increased brain concentration of GABA were examined on anesthesia in mice. To increase the GABA concentration of the brain, the GABA-transaminase inhibitor gabaculine and the GABA uptake inhibitor NO-711 were administered intraperitoneally. General anesthetic action was evaluated using two procedures as the different end point ; a loss of the righting reflex (LORR) and a loss of the tail-pinch response. The LORR may reflect unconsciousness, and the loss of the tail-pinch response may reflect the integrated components of anesthesia. Gabaculine dose-dependently induced LORR with an ED_<50> value of 100 (75-134) mg/kg, but the highest dose (400 mg/kg) used in this study did not produce any loss of the tail-pinch response. In a brain microdialysis study, gabaculine (100 mg/kg) significantly increased extracellular GABA level (up to 3179.0% ^^+__- 314.9%) in the hippocampus. A high dose of NO-711 (50 mg/kg) induced ataxia, but produced neither the LORR nor the loss of the tail-pinch response. Increase in extracellular GABA level induced by NO-711 (50 mg/kg) was only 269.7% ^^+__- 24.2%. In contrast, the intravenous anesthetic propofol clinically used induced both the loss of the righting reflex and the tail-pinch response. In a previous study, we reported that propofol-induced anesthesia is mediated, at least in part, by both GABA and glutamate neurons. These findings suggest that general anesthetic action may be induced by the combination of enhancing inhibitory neurotransmission and inhibiting excitatory neurotransmission.