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-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.
Witkin
Jeffrey M
JM
Drug Development Group, Addiction Research Center, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA. jwitkin@lilly.com
Gasior
Maciej
M
Schad
Christina
C
Zapata
Agustin
A
Shippenberg
Toni
T
Hartman
Theresa
T
Slusher
Barbara S
BS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D003042:Cocaine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000523:psychology; D043425:Glutamate Carboxypeptidase II; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
C402107:2-(phosphonomethyl)pentanedioic acid; D000927:Anticonvulsants; D003292:Convulsants; D018765:Dopamine Uptake Inhibitors; D009943:Organophosphorus Compounds; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D003042:Cocaine