Reduction of inhibition by a benzodiazepine antagonist, Ro15-1788, in the rat hippocampal slice.

The effects of extracellular applications of benzodiazepine agonists and the benzodiazepine antagonist, Ro15-1788, were investigated on pyramidal neurons in the CA1 region of rat hippocampal slices. The benzodiazepine agonists, chlordiazepoxide and diazepam, enhanced gamma-aminobutyrate synaptic inhibition, as tested by extracellular recordings during a paired-pulse inhibition paradigm. In contrast, Ro15-1788 (0.1-1 microM) depressed paired-pulse inhibition in a dose-dependent manner that suggested agonist activity at higher (10-100 microM) concentrations. Intracellular recordings from CA1 neurons showed that Ro15-1788 reduced both orthodromically and antidromically evoked inhibitory postsynaptic potentials. The reduction of the inhibitory postsynaptic potential probably resulted from a postsynaptic effect on the conductance mechanism of the inhibitory postsynaptic potential, since there were no changes in resting input resistance, the inhibitory postsynaptic reversal potential or the frequency of spontaneous inhibitory postsynaptic potentials. These data suggest that in the hippocampal slice preparation either (1) an endogenous benzodiazepine agonist exists that can be displaced by Ro15-1788 or (2) Ro15-1788 has inverse agonist activity.