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HCN1-mediated interactions of ketamine and propofol in a mean field model of the EEG
BMC Neuroscience volume 14, Article number: O22 (2013)
Ketamine and propofol, two popular anesthetic agents, are generally believed to operate via disparate primary mechanisms: ketamine through NMDA antagonism and propofol through the potentiation of GABAA-gated receptor currents. However, surprisingly the effect of ketamine on the EEG is markedly altered in the presence of propofol. Specifically, while ketamine alone results in a downshift of the peak frequency of the alpha rhythm, and propofol keeps it roughly constant - when administered together, they increase the alpha peak frequency [1].
Recently it has been found that both ketamine and propofol inhibit the hyperpolarization-activated cyclic nucleotide-gated potassium channel form 1 (HCN1) subunits, which induces neuronal membrane hyperpolarization [2]. Furthermore, HCN1 knockout mice are significantly less susceptible to hypnosis with these agents; but equally affected by HCN1-neutral etomidate [2].
We show here [3] that an established mean field model of electrocortical activity can predict the EEG changes induced by combining ketamine and propofol by taking into account merely the HCN1-mediated hyperpolarisations, but neglecting their supposed main mechanisms of action (NMDA and GABAA, respectively). See Figure 1.
Our results suggest that ketamine and propofol are infra-additive in their HCN1-mediated actions. This is consistent with independent experimental evidence[4]. We show here that the HCN1-mediated actions of ketamine and propofol, hitherto neglected by models of anaesthetic action, can not only explain a range of counterintuitive induced EEG changes but also predicts the infra-additivity of these drugs.
References
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Chen X, Shu S, Bayliss DA: HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci. 2009, 29 (3): 600-609. 10.1523/JNEUROSCI.3481-08.2009.
Bojak I, Day HC, Liley DTJ: Ketamine, propofol and the EEG: a neural field analysis of HCN1-mediated interactions. Front Comput Neurosci.
Hendrickx JF, Eger EI, Sonner JM, Shafer SL: Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility. Anesth Analg. 2008, 107 (2): 494-506. 10.1213/ane.0b013e31817b859e.
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Bojak, I., Day, H.C. & J Liley, D.T. HCN1-mediated interactions of ketamine and propofol in a mean field model of the EEG. BMC Neurosci 14 (Suppl 1), O22 (2013). https://doi.org/10.1186/1471-2202-14-S1-O22
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DOI: https://doi.org/10.1186/1471-2202-14-S1-O22