Attenuation of cocaine kindling by 7-nitroindazole, an inhibitor of brain nitric oxide synthase

Abstract

Recent studies suggest the involvement of the N-methyl-D-aspartate (NMDA) type of glutamate receptors and nitric oxide synthase (NOS) in the process of increased sensitivity to the convulsive effect of cocaine (“cocaine kindling”). The present study was undertaken to analyze the various behavioral stages in the development of cocaine kindling and to investigate the effect of 7-nitroindazole (7-NI), a relatively selective inhibitor of the neuronal NOS isoform, on the induction and expression of sensitization to the convulsive effect of cocaine. Also, the effect of 7-NI on responses produced by acute systemic administration of cocaine or N-methyl-D-aspartate (NMDLA) was investigated. Cocaine kindling was assessed on a five-stage scale following the administration of a sub-convulsant dose of the drug (35 mg/kg/day; i.p.) to Swiss Webster mice for 10 days. Stage 5 seizures developed following the 9th day of cocaine administration. Pre-treatment with 7-NI (25 mg/kg/day; i.p.) 15 min before cocaine for 10 days completely prevented the appearance of stage 4 and 5 seizures, and it significantly attenuated stage 3 behavior in response to a challenge cocaine dose (35 mg/kg) given either 24 hr or 10 days after 7-NI/cocaine administration was stopped. A single injection of 7-NI (25 mg/kg; i.p.) completely prevented the expression of cocaine kindled seizures. Whereas 7-NI had no effect on the responses elicited by acute cocaine administration (60 mg/kg; i.p.), this agent partially attenuated the effects induced by systemic administration of the NMDA receptor agonist NMDLA (250 mg/kg; i.p.). The present study indicates that 7-NI attenuates both the induction and expression of sensitization to the convulsive effect of cocaine. The findings that 7-NI attenuated cocaine kindling and partially blocked the effects produced by activation of the NMDA receptor, but not the effects induced by acute cocaine administration, support the role of the NMDA receptor and brain NOS in the development of cocaine kindling rather than in the acute effects of the drug.