Blockade of Sensitization to the Toxic Effects of Cocaine in Mice by Nitric Oxide Synthase Inhibitors

Repeated administration of cocaine to animals results in sensitization to several reactions to the drug, including seizures and mortality. These consequences are thought to be related to the pathology that develops in humans abusing cocaine. Previous studies implied the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors in cocaine-induced toxicity, and recent studies documented a role for nitric oxide in NMDA-receptor mediated neurotoxicity. The present study was undertaken to determine whether nitric oxide synthase inhibitors block the development of sensitization to the toxic effects of cocaine in mice. Repeated administration of cocaine (45 mg/kg/day; intraperitoneally) to Swiss Webster mice, for 7 days, resulted in a progressive increase in the duration of the convulsive response to cocaine, an increase in the number of animals that had seizures, and augmentation in lethality rate. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/day; intraperitoneally) or NG-nitro-L-arginine (NO-Arg; 25 mg/kg/day; intraperitoneally) completely abolished the sensitization to the convulsive and lethal responses to cocaine. Receptor binding assays indicated first, that pretreatment with L-NAME apparently diminished cocaine-induced upregulation of cortical NMDA receptors, and second, that the effects of the nitric oxide synthase inhibitors tested are not mediated via a direct interaction of the drugs with the phencyclidine/NMDA receptor complex. Taken together, the present study suggests an important role for nitric oxide in the development of sensitization to the toxic effects of cocaine, and further supports the relationship between NMDA-receptor mediated neurotoxicity and nitric oxide.