NAALADase (GCP II) inhibition prevents cocaine-kindled seizures

Jeffrey M. Witkin, Maciej Gasior, Christina Schad, Agustin Zapata, Toni Shippenberg, Theresa Hartman, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

Abstract

The prediction that inhibition of NAALADase, an enzyme catalyzing the cleavage of glutamate from N-acetyl-aspartyl-glutamate, would produce antiepileptogenic effects against cocaine was tested. Cocaine 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.

Original languageEnglish (US)
Pages (from-to)348-356
Number of pages9
JournalNeuropharmacology
Volume43
Issue number3
DOIs
StatePublished - Sep 2002
Externally publishedYes

Keywords

  • Cocaine
  • Mice
  • NAAG
  • NAALADase inhibition
  • Seizure kindling

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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