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Journal of Neuroscience, Vol 5, 2365-2373, Copyright © 1985 by Society for Neuroscience
Modulation of neurotransmitter action: control of the gamma- aminobutyric acid response through the benzodiazepine receptor
CY Chan and DH Farb
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.
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