Dihydropicrotoxinin binding sites in mammalian brain: interaction with convulsant and depressant benzodiazepines.

The specific binding of [3H] alpha-dihydropicrotoxinin to rat brain membranes was inhibited competitively and potently (IC50 congruent to 100 nM) by a convulsant benzodiazepine drug, RO5-3663. This compound did not inhibit high affinity flunitrazepam binding to the same tissue under similar conditions, and its reported pharmacological activity as an antagonist of GABAergic synaptic transmission, which resembles that of picrotoxinin, appears to involve the picrotoxinin binding sites. Other benzodiazepines such as diazepam, in micromolar concentrations, inhibited picrotoxinin binding in a stereospecific and chemically specific manner. However, the order of potency of a series of depressant benzodiazepines did not correlate well with pharmacological activities nor with reported activities for displacement of high affinity benzodiazepine 'receptor' binding sites (although heterogeneity of both picrotoxinin and benzodiazepine binding site populations may make difficult such comparisons). A comparison of benzodiazepine-displaceable benzodiazepine binding and benzodiazepine-displaceable picrotoxinin binding for different brain regions and subcellular fractions revealed a very similar though not identical distribution of these two classes of drug receptor, again suggesting that the two are not identical. Both classes of drug binding site also showed a very similar distribution to sodium-independent GABA receptor binding sites, which is consistent with other evidence that at least part of these 3 receptor types may be found at least sometimes coupled together in the postsynaptic membrane GABA receptor-ionophore complex.