Paradoxical facilitation of pilocarpine-induced seizures in the mouse by MK-801 and the nitric oxide synthesis inhibitor L-NAME

Abstract

The sensitivity of pilocarpine-induced seizures to NMDA receptor blockade with MK-801, or to inhibition of synthesis of the second messenger nitric oxide (NO) with N omega-nitro-L-arginine methyl ester (L-NAME), was studied in mice. The NO precursor L-arginine (100-500 mg/kg, IP) and L-NAME (1-125 mg/kg, IP) had no overt effects on animals' behaviour by themselves, while MK-801 (0.1-0.8 mg/kg, IP) caused motor excitability at low doses and sedation and paraplegia at high ones. Contrary to expectation, MK-801 and L-NAME failed to protect mice against limbic motor seizures induced by pilocarpine (400 mg/kg, IP), and L-arginine was not proconvulsant in mice challenged with a threshold convulsant dose of the cholinomimetic (100 mg/kg, IP). Surprisingly, both MK-801 and L-NAME were found to be proconvulsant when injected in conjunction with 100 mg/kg pilocarpine, and in both cases this convulsant action synergised with that produced by the dopamine D1 agonist SK&F38393 (10 mg/kg, IP). Concomitant administration of L-arginine (500 mg/kg) prevented the convulsant effect of 5 mg/kg L-NAME but was ineffective against 25 mg/kg L-NAME and MK-801. It is concluded that glutamate, acting through the NMDA receptor and NO production, normally suppresses epileptogenesis in the mouse pilocarpine model of limbic epilepsy.