NAALADase (GCP II) inhibition prevents cocaine-kindled seizures.

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.

• Authors: Jeffrey M Witkin, Maciej Gasior, Christina Schad, Agustin Zapata, Toni Shippenberg, Theresa Hartman, Barbara S Slusher
• Journal: Neuropharmacology (Neuropharmacology) Vol. 43 Issue 3 Pg. 348-56 (Sep 2002) ISSN: 0028-3908 [Print] England
• PMID: 12243764 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(phosphonomethyl)pentanedioic acid
• Anticonvulsants
• Convulsants
• Dopamine Uptake Inhibitors
• Organophosphorus Compounds
• Carboxypeptidases
• Glutamate Carboxypeptidase II
• Cocaine

Topics

• Animals
• Anticonvulsants (pharmacology)
• Behavior, Animal (drug effects)
• Carboxypeptidases (antagonists & inhibitors)
• Cocaine (administration & dosage, antagonists & inhibitors, pharmacology)
• Convulsants (administration & dosage, pharmacology)
• Dopamine Uptake Inhibitors (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Epilepsy, Tonic-Clonic (chemically induced, psychology)
• Glutamate Carboxypeptidase II
• Kindling, Neurologic (drug effects)
• Male
• Mice
• Organophosphorus Compounds (pharmacology)
• Seizures (chemically induced, prevention & control)