ACUTE EFFECTS OF MK801 ON KAINIC ACID-INDUCED SEIZURES IN NEONATAL RATS

Kainic acid (KA) causes behavioral and electrographic status epileptic us (SE) in rats of all ages. In adult rats, the noncompetitive N-methy l-D-aspartate (NMDA) channel blocker MK801 11-dihydro-5H-dibenzo[a,d]- cyclohepten-5,10-imine) is anticonvulsant against KA-induced seizures: it reduces their severity and protects against neuronal damage, altho ugh it may worsen electrographic seizures. Here we examined the effect s of MK801 on KA seizures in the immature brain. Neonatal rats (P11-P1 2) were pretreated with MK801 (0.01, 0.1, 0.5 or 1.0 mg/kg, i.p.) or s aline twenty minutes prior to KA (2 mg/kg, i.p.). Clinical seizure beh avior was monitored for > 6 hrs, and in some rats the EEG was monitore d with an intrahippocampal or intracortical electrode. MK801 caused im mobility alternating with hyperactivity, ataxia, scratching and someti mes alternate limb cycling, which correlated with the appearance of sp ikes on the EEG. Compared to KA alone or KA preceded by 0.01 mg/kg MK8 01, the higher doses of MK801 (0.1, 0.5 and 1.0 mg/kg) significantly l owered the latency to electrographic seizures (P < 0.001), ictal scrat ching (P < 0.0001), and status epilepticus (P < 0.0001). MK801 pretrea tment did not lower significantly the death rate due to KA seizures. N o histologic damage was seen after MK801, KA or both agents together. These results suggest that MK801 exacerbates KA-induced seizures in th e neonatal brain, and may even cause ictal behavioral and electrograph ic manifestations by itself. The findings point to an age-dependency o f NMDA antagonist action, and suggest caution in considering the use o f NMDA antagonists in neonates. (C) 1997 Elsevier Science B.V.