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SUB-MAC CONCENTRATIONS OF ISOFLURANE TARGET NOVEL MURINE GABA_ARs

^a Departments of Anesthesia, Sunnybrook & Women’s College Health Sciences Centre,
^b Physiology,
^c Institute of Medical Sciences, and
^d Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada

INTRODUCTION

Sub-anesthetic concentrations of propofol, midazolam and volatile anesthetics produce amnesia without causing sedation, immobility and unconsciousness.^1–2 The mechanisms by which sub-anesthetic concentrations produce amnesia are unknown. It is believed that enhancement of inhibitory current mediated by synaptic GABA_A receptors (GABA_ARs) is the predominant mechanism of action of most anesthetics. Our laboratory showed that an extrasynaptic tonic inhibitory conductance in hippocampal neurons is sensitive to low concentrations of intravenous anesthetics³ . Here, we test the hypothesis that the tonic inhibitory conductance is highly sensitive to volatile anesthetics due to the unique subunit composition of the underlying GABA_ARs.

METHODS

Animal protocols were approved by the University of Toronto Animal Care Committee. Whole-cell currents were recorded from HEK 293 cells transfected with human GABA_ARs cDNA ( 1ß3 2L or 5ß3 2L), and from cultured hippocampal neurons obtained from wild-type and genetically modified mice lacking the 5-subunit of the GABA_ARs ( 5-/- knock-out mice). Data are expressed as mean ± SEM and p<0.05 was considered significant.

RESULTS

Sub-MAC concentrations of isoflurane (25 µM; 0.1 MAC) reversibly enhanced the tonic current (166 ± 24.9%, n = 10, p < 0.01). Moreover, results from transfected HEK 293 cells and hippocampal neurons of 5-/- knock-out mice indicate that isoflurane enhanced the tonic conductance by selectively targeting GABA_ARs containing the 5 subunit.

DISCUSSION

Volatile anesthetics can cause amnesia at concentrations well below those required to cause sedation, unconsciousness and immobility. These results suggest that volatile anesthetics induce the amnestic effects through enhancement of the tonic current in hippocampal neurons by targeting 5-containing GABA_ARs. Our data also implicate the 5-containing GABA_ARs as playing a critical role in learning and memory processes⁴.

REFERENCES

1 Anesthesiology 95: 896–907

2 Anesth Analg 57: 434–440

3 Mol Pharm 59: 814–824

4 J Neurosci 22: 5572–5580

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