Ro 5-4864, like picrotoxin, enhances EPSP-spike coupling in the freely behaving rat

To help determine its mechanism of action, the convulsant benzodiazepine Ro 5-4864 was administered (15-20 mg/kg) intraperitoneally (IP) and electrophysiological and behavioral effects were compared; parallel studies were conducted with picrotoxin (PTX; 1 mg/kg). Both PTX and Ro 5-4864 produced myoclonic seizures, primarily between 15-40 min after administration; myoclonus was followed by more severe seizures after PTX. Both Ro 5-4864 and PTX produced a maximal increase in amplitude and decrease in threshold of the population spike (PS) evoked in the dentate gyrus (DG) by stimulation of the dorsal perforant path prior to peak seizure activity; start latency of the PS and initial slope and amplitude of the population slow wave (SW) were not changed. Amplitude of the PS was already increased by 5 min after administration of Ro 5-4864 and was maximally increased 1.8- to 3-fold, depending on stimulus intensity, usually by 10 min. Similarly, by 20 min after administration, PTX had also increased PS amplitude in the absence of an effect on PS latency or the SW. The increase in PS amplitude without concomitant changes in the SW suggests that Ro 5-4864 enhanced coupling between the excitatory postsynaptic potential (EPSP) and firing of the postsynaptic neurons, i.e., it enhanced E-S coupling, as has also been suggested for PTX. The similarity in the effects of Ro 5-4864 and PTX suggests that antiGABAergic effects, perhaps along feedforward inhibitory pathways, are involved in both the seizures and enhanced E-S coupling.