Modulation of neurotransmitter action: control of the gamma-aminobutyric acid response through the benzodiazepine receptor.

The ability of several homologous benzodiazepine and heterologous nonbenzodiazepine ligands to alter the conductance increase induced in spinal cord neurons by gamma-aminobutyric acid (GABA) was determined. Complete dose-response curves were carried out on individual neurons, reducing error introduced by cell-to-cell variability. The efficacies of modulation differ for "classical" benzodiazepines and novel nonbenzodiazepine drugs in a manner consistent with a model of control of GABA receptor action through a common receptor. There was no apparent correlation between efficacy and potency. CL 218,872, a triazolopyridazine, gave the lowest efficacy of the tranquilizers tested. Ro 15-1788 (an imidazobenzodiazepine) potentiated g GABA with high potency and low efficacy, consistent with an action as a partial agonist and an "antagonist" of classical benzodiazepine action. In order of increasing efficacy, Ro 15-1788, CL 218,872, and flurazepam are partial agonists, whereas clonazepam, chlordiazepoxide, diazepam, and flunitrazepam are full agonists. The beta-carboline drugs methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) are "anxiogenics" and convulsants that were found to exert through the benzodiazepine receptor-inhibitory and apparently insurmountable control of g GABA . beta-CCM and DMCM display large negative efficacies and act like effectors at a site distinct from the picrotoxin-sensitive chloride ionophore and coincident with the benzodiazepine site. The actions of these different benzodiazepine receptor ligands in vivo range from anxiolytic and anticonvulsant to anxiogenic and convulsant. Efficacy rather than potency almost certainly determines the qualitative nature of the pharmacological actions of these drugs.