Is the picrotoxinin binding site at the GABA synapse a site of action for barbiturates

The molecular mechanisms involved in barbiturate action have yet to be elucidated. Recent neurophysiological studies suggest a possible involvement of GABA synaptic events in barbiturate action. Our studies indicate that the racemic barbiturates inhibit the binding of GABA synaptic antagonist, (³H) α-dihydropicrotoxinin (DHP), to rat brain membrane. Several lines of evidence suggest that DHP binding is associated with GABA receptor-ionophores, but is distinct from the GABA receptor sites. Thus, depressant barbiturates like secobarbital (IC₅₀=5 μM), hexobarbital (IC₅₀= 12 μM) and pentobarbital (IC₅₀ = 50 μM) inhibit DHP binding in the micromolar range. The interaction between pentobarbital and DHP appears to be competitive. DHP binding is also displaced by convulsant barbiturates and stereoisomers of the depressant barbiturates. The displacement curves obtained with convulsant barbiturates deviate from the Law of Mass Action, suggesting possible heterogenity of DHP binding sites. Stereoisomers of 1-methyl-5-phenyl-propylbarbituric acid (MPPB), which produce opposite pharmacological effects, inhibited DHP binding with a 10-fold difference. These findings are consistent with the neurophysiological evidence that depressant and convulsant action of barbiturates may be related to their modulation of GABA mediated inhibitory transmission. The possibility that depressant and convulsant barbiturates may modulate GABA receptor linked chloride ionophores is discussed.