PROTECTION BY NMDA RECEPTOR ANTAGONISTS AGAINST SEIZURES INDUCED BY INTRACEREBRAL ADMINISTRATION OF 4-AMINOPYRIDINE

The effects of NMDA receptor antagonists on the convulsant action of t he administration of l-aminopyridine in the rat lateral cerebral ventr icle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) we re studied. 4-Aminopyridine administration in both regions induced var ious preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c .v. injection, running fits and generalized tonic convulsions. This be havioral pattern appeared 5-9 min after administration of 4-aminopyrid ine and persisted for 100-150 min. 4-Aminopyridine also generated epil eptiform electroencephalographic (EEG) discharges characterized by iso lated spikes, poly-spikes and spike-wave complexes, which began some s econds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists -)-3-(2-carboxy-piperazi-4-yl)-pro pyl-1-phosphonic acid (CPP), (+/-)-2-amino-7-phosphono-heptanoic acid (AP7) and 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alte rations induced by i.c.v. 4-aminopyridine, particularly the tonic conv ulsions, but were less effective against those produced by i.cx. 4-ami nopyridine. These antagonists also delayed the appearance of EEG epile ptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-ami nopyridine. These results, together with previous data showing that 4- aminopyridine stimulates the release of glutamate in vivo, suggest tha t an excessive glutamatergic neurotransmission involving NMDA receptor s is implicated in 4-amino-pyridine-induced seizures.