PD117302, An Opioid Kappa Agonist, and MK801 Partially Block Maximal ElectroshockConvulsion-Induced Increases in c-fos mRNA in Rat Brain

摘要

It has been known that seizure activity is associated with increases in the proto-oncogene c-fos mRNA and c-fos protein in brain. The present study was undertaken to determine if the novel anticonvulsant kappa opioid drug, PD117302, and the NMDA antagonist MK801, would block seizure-induced c-fos mRNA in rat brain. c-fos MRNA levels, measured by Northern blot analysis, were greatly increased in a time-dependent manner following maximal electroshock (MES). Increased levels were measured within 15 min after MES, reaching a maximum in 30 min and declining to control levels within 2h post-convulsion. A maximal stimulation in c-fos mRNA of 10-15 fold was observed in the cerebellum, followed by hippocampus (5-7 fold) and cerebral cortex (4-6 fold). Administration of anticonvulsant doses of PD117302 (16 and 32 mg/kg, s.c.) and MK801 (0.2, 1.0 and 2.0 mg/kg. s.c.) alone produced no significant changes in c-fos MRNA levels in these three brain areas. However, both drugs (PDl 17302, 32mg/kg; MK801, 0.2mg/kg) administered 30 min prior to MES significantly blocked c-fos MRNA induction with the greatest effect observed in the cerebellum and a minimum effect in the cerebral cortex. Seizure-induced increases in c-fos mRNA levels and its partial blockade by anticonvulsant drugs suggest a possible role of c-fos in the mechanism of action of these drugs.