HIPPOCAMPAL GABA(A) CHANNEL CONDUCTANCE INCREASED KY DIAZEPAM

Benzodiazepines, which are widely used clinically for relief of anxiet y and for sedation(1), are thought to enhance synaptic inhibition in t he central nervous system by increasing the open probability of chlori de channels activated by the inhibitory neurotransmitter gamma-aminobu tyric acid (GABA)(2,3). Here we show that the benzodiazepine diazepam tan also increase the conductance of GABA(A) channels activated by low concentrations of GABA (0.5 or 5 mu M) in rat cultured hippocampal ne urons. Before exposure to diazepam, chloride channels activated by GAB A had conductances of 8 to 53 pS. Diazepam caused a concentration-depe ndent and reversible increase in the conductance of these channels tow ards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the condu ctance of GABA(A) channels tonically activated by low ambient concentr ations of GABA in the extracellular environment(4) maybe an important way in which these drugs depress excitation in the central nervous sys tem. That any drug has such a large effect on single channel conductan ce has not been reported previously and has implications for models of channel structure and conductance.