NAALADase (GCP II) inhibition prevents cocaine-kindled seizures

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutaillate, would produce antiepileptogenic effects against cocaine was tested. Cocame kindled seizures were developed in male, Swiss-Webster mice by daily administration of 60 mg/kg. cocaine for 5 days. The NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA)produced dose-dependent protection (10-100 mg/kg) against both the development of seizure kindling and the occurrence of seizures during the kindling process without observable behavioral side-effects. It is not likely that 2-PMPA produced protection against cocaine kindling by altering the potency of the convulsant Stimulus as daily administration of 2-PMPA did not alter the convulsant thresholds for cocaine. Lower daily doses of cocaine (40 mg/kg) did not increase the incidence of seizures but produced kindling, as evidenced by the increase in seizure susceptibility when mice were probed with a higher dose of cocaine. 2-PMPA was also effective in preventing the development of sensitization to this covert kindling process. In contrast to its efficacy against cocaine kindled seizures, 2-PMPA failed to attenuate the convulsions engendered by acute challenges with pentylenetetrazole, bicuculline, N-methyl-D-aspartate, maximal electroshock or cocaine. Similarly, acutely-administered 2-PMPA did not block cocaine seizures in fully-kindled mice. NAALADase inhibition thus provides a novel means of attenuating the development of cocaine seizure kindling. (C) 2002 Elsevier Science Ltd. All rights reserved.