Electrophysiological studies on benzodiazepine antagonists

The actions of the benzodiazepine (BDZ) antagonists 3-hydroxymethyl-beta-carboline (3-HMC), Ro 14-7437 and Ro 15-1788 were tested on single cell activity of rat hypothalamic neurons in tissue cultures and on membrane properties of CA1 hippocampal pyramidal neurons in transverse slices. In addition, we examined the interactions of some of these agents with inhibitions elicited by gamma-aminobutyric acid (GABA) as well as the ability of Ro 14-7437 to reverse the GABA-enhancing action of the BDZ agonist flurazepam. BDZ antagonists did not alter patterns of spontaneous activity of hypothalamic neurons and did not affect resting membrane potential or membrane conductance in CA1 pyramidal cells. Ro 14-7437 either partially or totally reversed the potentiation by flurazepam of GABA-elicited depression of hypothalamic neuronal activity. Small and inconsistent actions on GABA-mediated inhibitions of hypothalamic neurons were noted. Electrically-elicited inhibitions of hypothalamic neurons were either not altered or slightly reduced. In the hippocampal slice, the frequency of spontaneous IPSPs, the amplitude of stratum-radiatum evoked IPSPs and the conductance increase caused by stratum-radiatum stimulation were either not altered or slightly reduced. These findings demonstrate that non-convulsant BDZ antagonists block the action of BDZ agonists in facilitating GABA and further that the presence of a BDZ agonist is not required for these GABA-mediated events to occur. However, these experiments do not exclude a modulatory role for an endogenous BDZ agonist on GABA-mediated events.