Inhibition of GABA metabolism in rat brain synaptosomes by midazolam (RO-21-3981).

Benzodiazepines are known to potentiate GABA (gamma aminobutyric acid) action in the brain. The effects of midazolam, a water-soluble benzodiazepine, on GABA disposal (14CO2 from [1-14C]GABA) and on the individual processes of GABA uptake, GABA release, and GABA-transaminase in the rat brain synaptosomal model system were studied. A 10 per cent inhibition of action was defined as ID10. Midazolam inhibited overall GABA disposal at ID10 = 13 micro M. The ID10 values for the three contributing process in the overall GABA disposal process are 580 micro M for GABA-transaminase activity, 96 micro M for GABA release, and 13 micro M for GABA uptake. The value for GABA release is probably not valid since it fell outside of the linear part of the regression line which was used for calculation. Therefore, GABA uptake inhibition appears to be responsible for the overall inhibition of GABA disposal. This value is consistent with the proposed hypothesis that anesthesia involves excess GABA in the synaptic area.