Centre for Computational Neuroscience and Cognitive Robotics, School of Psychology, University of Birmingham Birmingham, UK ; Donders Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre Nijmegen, Netherlands.
Front Comput Neurosci. 2013 Apr 5;7:22. doi: 10.3389/fncom.2013.00022. eCollection 2013.
Ketamine and propofol are two well-known, powerful anesthetic agents, yet at first sight this appears to be their only commonality. Ketamine is a dissociative anesthetic agent, whose main mechanism of action is considered to be N-methyl-d-aspartate (NMDA) antagonism; whereas propofol is a general anesthetic agent, which is assumed to primarily potentiate currents gated by γ-aminobutyric acid type A (GABAA) receptors. However, several experimental observations suggest a closer relationship. First, the effect of ketamine on the electroencephalogram (EEG) is markedly changed in the presence of propofol: on its own ketamine increases θ (4-8 Hz) and decreases α (8-13 Hz) oscillations, whereas ketamine induces a significant shift to beta band frequencies (13-30 Hz) in the presence of propofol. Second, both ketamine and propofol cause inhibition of the inward pacemaker current I h, by binding to the corresponding hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) subunit. The resulting effect is a hyperpolarization of the neuron's resting membrane potential. Third, the ability of both ketamine and propofol to induce hypnosis is reduced in HCN1-knockout mice. Here we show that one can theoretically understand the observed spectral changes of the EEG based on HCN1-mediated hyperpolarizations alone, without involving the supposed main mechanisms of action of these drugs through NMDA and GABAA, respectively. On the basis of our successful EEG model we conclude that ketamine and propofol should be antagonistic to each other in their interaction at HCN1 subunits. Such a prediction is in accord with the results of clinical experiment in which it is found that ketamine and propofol interact in an infra-additive manner with respect to the endpoints of hypnosis and immobility.
氯胺酮和丙泊酚是两种众所周知的强效麻醉剂,但乍一看,这似乎是它们唯一的共同点。氯胺酮是一种分离麻醉剂,其主要作用机制被认为是 N-甲基-D-天冬氨酸(NMDA)拮抗作用;而丙泊酚是一种全身麻醉剂,主要作用是增强γ-氨基丁酸 A 型(GABAA)受体门控电流。然而,一些实验观察表明它们之间存在更密切的关系。首先,丙泊酚的存在显著改变了氯胺酮对脑电图(EEG)的影响:氯胺酮本身增加θ(4-8 Hz)并减少α(8-13 Hz)振荡,而在丙泊酚存在下,氯胺酮诱导明显的β频段频率(13-30 Hz)转移。其次,氯胺酮和丙泊酚通过与相应的超极化激活环核苷酸门控钾通道 1(HCN1)亚基结合,均导致内向起搏电流 I h 抑制。其结果是神经元的静息膜电位超极化。第三,HCN1 敲除小鼠中氯胺酮和丙泊酚诱导催眠的能力降低。在这里,我们表明,仅基于 HCN1 介导的超极化,就可以从理论上理解观察到的 EEG 光谱变化,而无需分别涉及这些药物的 NMDA 和 GABAA 假定的主要作用机制。基于我们成功的 EEG 模型,我们得出结论,氯胺酮和丙泊酚在 HCN1 亚基上的相互作用应该是拮抗的。这种预测与临床实验结果一致,即在催眠和不动点方面,发现氯胺酮和丙泊酚的相互作用呈次相加方式。