Chronic treatment with a benzodiazepine agonist in vivo increases the actions of the benzodiazepine partial inverse agonist, FG7142, on the hippocampal slice in vitro.

We have shown previously that chronic treatment of mice with a benzodiazepine agonist, flurazepam, increased the pharmacological actions of the partial inverse agonist, FG7142. We have investigated the neurophysiological basis for this using extracellular recordings of evoked field potentials in area CA1 of isolated hippocampal slices. The slices were prepared 48 h after the end of the chronic in vivo treatment, a time when no evidence of residual benzodiazepine agonist activity was found in the CNS. During perfusion with standard Ringer solution, no significant differences were seen between the field potentials in slices from flurazepam-treated mice and those from control animals. When FG7142 was added to the perfusion medium there was an increase in the secondary discharges that followed the initial population spikes, and an increase in paired pulse potentiation. These increases were significantly greater in slices from flurazepam-treated mice, compared with controls. The results show that the effects of the partial inverse agonist, FG7142, on an isolated neuronal preparation, were increased by chronic administration of a benzodiazepine agonist in vivo. This effect is suggested to be due to a decrease in GABAergic inhibition.