Document Detail

Forebrain HCN1 channels contribute to hypnotic actions of ketamine.
MedLine Citation:
PMID:  23377220     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Ketamine is a commonly used anesthetic, but the mechanistic basis for its clinically relevant actions remains to be determined. The authors previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are twofold less sensitive to hypnotic actions of ketamine. Although that work identified HCN1 channels as a viable molecular target for ketamine, it did not determine the relevant neural substrate.
METHODS: To localize the brain region responsible for HCN1-mediated hypnotic actions of ketamine, the authors used a conditional knockout strategy to delete HCN1 channels selectively in excitatory cells of the mouse forebrain. A combination of molecular, immunohistochemical, and cellular electrophysiologic approaches was used to verify conditional HCN1 deletion; a loss-of-righting reflex assay served to ascertain effects of forebrain HCN1 channel ablation on hypnotic actions of ketamine.
RESULTS: In conditional knockout mice, HCN1 channels were selectively deleted in cortex and hippocampus, with expression retained in cerebellum. In cortical pyramidal neurons from forebrain-selective HCN1 knockout mice, effects of ketamine on HCN1-dependent membrane properties were absent; notably, ketamine was unable to evoke membrane hyperpolarization or enhance synaptic inputs. Finally, the EC50 for ketamine-induced loss-of-righting reflex was shifted to significantly higher concentrations (by approximately 31%).
CONCLUSIONS: These data indicate that forebrain principal cells represent a relevant neural substrate for HCN1-mediated hypnotic actions of ketamine. The authors suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine-induced hypnosis.
Cheng Zhou; Jennifer E Douglas; Natasha N Kumar; Shaofang Shu; Douglas A Bayliss; Xiangdong Chen
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anesthesiology     Volume:  118     ISSN:  1528-1175     ISO Abbreviation:  Anesthesiology     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-20     Completed Date:  2013-05-20     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  1300217     Medline TA:  Anesthesiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  785-95     Citation Subset:  AIM; IM    
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MeSH Terms
Analgesics / pharmacology*
Cyclic Nucleotide-Gated Cation Channels*
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Hypnotics and Sedatives / pharmacology*
Ketamine / pharmacology*
Mice, Transgenic
Potassium Channels*
Prosencephalon / drug effects*
Grant Support
Reg. No./Substance:
0/Analgesics; 0/Cyclic Nucleotide-Gated Cation Channels; 0/Hcn1 protein, mouse; 0/Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; 0/Hypnotics and Sedatives; 0/Potassium Channels; 690G0D6V8H/Ketamine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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