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Hippocampal GABAAchannel conductance increased by diazepam

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Abstract

Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation1, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter γ-aminobutyric acid (GABA)2,3. Here we show that the benzodiazepine diazepam can also increase the conductance of GABAAchannels activated by low concentrations of GABA (0.5 or 5 μM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53 pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70–80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAAchannels tonically activated by low ambient concentrations of GABA in the extracellular environment4 may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.

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Figure 1: The increase in single-channel current amplitude caused by 10 μM diazepam in a cell-attached patch (pipette potential of −80 mV).
Figure 2: A gradual increase in single-channel current amplitude caused by diazepam in an inside-out patch (pipette potential of −80 mV).
Figure 3: The influence of diazepam concentration on single-channel currents activated by 0.5 μM GABA.
Figure 4: The relation between diazepam concentration and average single-channel conductance in 5 inside-out patches.

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Acknowledgements

We thank Graeme Cox for discussion and helpful comments.

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Authors and Affiliations

  1. John Curtin School of Medical Research, PO Box 334

    M. Eghbali, J. P. Curmi, B. Birnir & P. W. Gage

  2. Australian National University, Canberra, 2601, ACT, Australia

    M. Eghbali, J. P. Curmi, B. Birnir & P. W. Gage

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  1. M. Eghbali
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  2. J. P. Curmi
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  3. B. Birnir
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  4. P. W. Gage
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Eghbali, M., Curmi, J., Birnir, B. et al. Hippocampal GABAAchannel conductance increased by diazepam. Nature 388, 71–75 (1997). https://doi.org/10.1038/40404

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