Metaphit‐Induced Audiogenic Seizure and Its Inhibition by MK‐801: Electroencephalographic and Behavioral Characterization

Summary: Adult male Wistar rats were subjected to intense sound stimulation from an electric bell (100 dB and 12 KHz for 60 s) after a single intraperitoneal (i.p. 50 mg/kg) injection of metaphit l‐(l‐/3 isothiocyanatophenyl‐cyclohexyl) piperidine. EEG recordings demonstrated appearance of paroxysmal activity and spike‐wave complexes from cortical electrodes, with frequency and amplitude increasing with time. Metaphit‐induced audiogenic seizures in the rats were tested 24 h after metaphit administration. The seizures consisted of wild running followed by clonic and tonic convulsions, and the seizure pattern could be elicited at hourly intervals for the next 24 h in all tested animals. Forty‐eight hours after metaphit administration, susceptibility to sound stimulation began to decrease gradually. The first component of seizure response to disappear was tonic extension, followed by disappearance of clonic convulsion; the last component to disappear was running behavior. Each behavioral seizure response had a characteristic EEG correlate. After ∼50 h, no animal responded to sound stimulation. The noncompetitive antagonist of the N‐methyl‐D‐aspartate (NMDA) receptors, MK‐801 5‐methyl‐10, ll‐dihydro‐5H‐dibenzo (a, d) cyclohepten‐5,10‐imine maleate was evaluated as an anticonvulsant against metaphit‐induced audiogenic seizures in two experiments. In the first experiment, MK‐801 was administered in a single dose of 0.5 mg/kg i.p. 23.5 h after metaphit injection and 30 min before sound stimulation, which completely blocked both the EEG and the behavioral response to sound stimulation for 37 h. After that time, seizure susceptibility began to appear and within 7 h reached a maximum, at which time all animals responded with a complete pattern of a severe seizure. During the next 5 h, seizure susceptibility began to abate gradually and disappeared completely 76 h after metaphit administration. The EEG and behavioral responses did not differ from those elicited in animals treated with metaphit alone. In the second experiment, MK‐801 (0.5 mg/kg i.p.) administered 30 min before metaphit did not protect the animals from the effects of metaphit but significantly reduced the incidence of clonic‐tonic seizures. EEG signs of seizure susceptibility and progressive increase in epileptic discharges were not suppressed by MK‐801. Results suggest that MK‐801 is an anticonvulsant rather than an antiepileptic agent in the metaphit‐induced audiogenic seizure model.