Benzodiazepine receptor ligand actions on GABA responses. Benzodiazepines, CL 218872, zopiclone.

The effects on GABA (4-aminobutyric acid) responses of several benzodiazepine and nonbenzodiazepine benzodiazepine receptor ligands were examined using mouse spinal cord neurons in dissociated cell culture. Diazepam, clonazepam and nitrazepam enhanced GABA responses potently at low nanomolar concentrations. Diazepam and clonazepam were most potent with significant enhancement at 1 nM and peak enhancement of 80.7 and 50.2% at 10 nM respectively. Nitrazepam was least potent with no significant enhancement at 1 nM and enhancement of only 20.7% at 10 nM. The benzodiazepine antagonist, Ro 15-1788, blocked enhancement by diazepam but also weakly enhanced GABA responses at low micromolar concentrations, suggesting partial agonist activity. The convulsant benzodiazepine, Ro 5-4864, did not enhance GABA responses at any concentration tested but antagonized GABA responses at 1 microM and above. Diazepam shifted GABA dose-response curves to the left by decreasing the apparent KD but without altering the apparent Vmax (Lineweaver-Burk analysis). Two nonbenzodiazepine anxiolytic/anticonvulsants, CL 218872 and zopiclone, were weak enhancers of GABA responses at high nanomolar concentrations. These results with benzodiazepines, CL 218872 and zopiclone are consistent with their anxiolytic and anticonvulsant profile in vivo and with studies of their effects upon low affinity GABA binding in vitro.