The Antispastic Triazole MDL 27531 Selectively Enhanced GABA-Activated Chloride Current in Spinal Cord Motorneurons

Abstract

The triazole MDL 27531, 4-methyl-3-methylsulfonyl-5-phenyl-4H-1,2,4-triazole was identified as an antispastic agent selective for protection against strychnine-induced seizures and hyperreflexia. These compounds did not displace the binding of [3H]muscimol, [3H]flunitrazepam or [35S]TBPS to the GABAA receptor. The present experiments were performed to better understand the mechanism of action of this compound. Whole cell and single channel patch clamp recordings were obtained from GABAA-receptor activated chloride channels using cultured murine spinal cord motorneurons or rat hippocampal pyramidal neurons. GABA (2-5 μM) or GABA plus MDL 27531 (100nM or 1μM) was applied from blunt micropipettes using positive pressure. In spinal motorneurons, the application of GABA plus MDL 27531 (100nM) potentiated GABA-activated chloride currents relative to GABA alone. However, GABA plus MDL 27531 (1μM) did not change or slightly reduced GABA-activated chloride currents. No increase in chloride current was observed with GABA plus MDL 27531 on hippocampal pyramidal neurons. These data indicate that MDL 27531 modulates GABA-activated chloride current selectively. This may be due to selective modulation of subunit configurations of the GABAA receptor. The effect observed with higher concentrations of MDL 27531 may reflect either the modulation of different subunit configurations of the GABAA receptor or interactive effects with additional binding sites. Preliminary studies indicate that MDL 27531 does not modulate glycine-activated chloride currents. Further studies are planned using cloned subunit configurations of the GABAA receptor complex.