Electrophysiology of benzodiazepine receptor ligands: multiple mechanisms and sites of action.
Electrophysiology of BZR ligands has been reviewed from different points of view. A great effort was made to critically discuss the arguments for and against the temporarily leading hypothesis of the mechanism of action of BZR ligands, the GABA hypothesis. As has been discussed at length in the present article, an impressive body of electrophysiological and biochemical evidence suggests an enhancement of GABAergic inhibition in CNS as a mechanism of action of BZR agonists. Biochemical data even indicate a physical coupling between GABA recognition sites and BZR which, together with the effector site build-up by Cl- channels, form a supramolecular GABAA/BZR complex. By binding to a specific site on this complex, BZR agonists allosterically increase and BZR inverse agonists decrease the gating of GABA-linked Cl- channels, whereas BZR antagonists bind to the same site without an appreciable intrinsic activity and block the binding and action of both agonists as well as inverse agonists. While this model is supported by many electrophysiological experiments performed with BZR ligands in higher nanomolar and lower micromolar concentrations, it does not explain much controversial data from animal behavior and, more importantly, is not in line with electrophysiological effects obtained with low nanomolar BZ concentrations. The latter actions of BZR ligands in brain slices occur within a concentration range compatible with concentrations of BZ observed in CSF fluid, which would be expected to be found in the biophase (receptor level) during anxiolytic therapy in man. Enhanced K+ conductance seems to be a suitable candidate for this effect of BZR ligands. This direct action on neuronal membrane properties may underlie the many electrophysiological observations with extremely low systemic doses of BZR ligands in vivo which demonstrated a depressant effect on spontaneous neuronal firing in various CNS regions. Skeletomuscular spasticity and epilepsy are two neurological disorders, where both the enhanced GABAergic inhibition and increased K+ conductance may contribute to the therapeutic effect of BZR agonists, since electrophysiological and behavioral studies strongly support GABA-dependent as well as GABA-independent action of BZR ligands elicited by low to intermediate doses of BZ necessary to evoke anticonvulsant and muscle relaxant effects. Somewhat higher doses of BZR ligands, inducing sedation and sleep, lead perhaps to the only pharmacologically relevant CNS concentrations (ca. 1 microM) which might be due entirely to increased GABAergic inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
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D000818:Animals; D001921:Brain / Q000502:physiology*; D004594:Electrophysiology; D009474:Neurons / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology*; D013116:Spinal Cord / Q000502:physiology*
D011963:Receptors, GABA-A