THE NEURONAL NITRIC-OXIDE SYNTHASE INHIBITOR, 7-NITROINDAZOLE, PROTECTS AGAINST METHAMPHETAMINE-INDUCED NEUROTOXICITY IN-VIVO

The present study was undertaken to investigate whether the relatively selective neuronal nitric oxide synthase (NOS) inhibitor, 7-nitroinda zole (7-NI), protects against methamphetamine (METH)-induced neurotoxi city. Male Swiss Webster mice received the following treatments (i.p.; q 3 h X 3): (a) vehicle/saline, (b) 7-NI (25 mg/kg)/saline, (c) vehic le/METH (5 mg/kg), and (d) 7-NI (25 mg/kg)/METH (5 mg/kg). On the seco nd day, groups (a) and (b) received two vehicle injections, and groups (c) and (d) received two 7-NI injections (25 mg/kg, each). Administra tion of vehicle/METH resulted in 68, 44, and 55% decreases in the conc entration of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanilli c acid, respectively, and a 48% decrease in the number of [H-3]mazindo l binding sites in the striatum compared with control values. Treatmen t with 7-NI (group d) provided full protection against the depletion o f dopamine and its metabolites and the loss of dopamine transporter bi nding sites. Administration of 7-NI/saline (group b) affected neither the tissue concentration of dopamine and its metabolites nor the bindi ng parameters of [H-3]mazindol compared with control values. 7-NI had no significant effect on animals' body temperature, and it did not aff ect METH-induced hyperthermia. These findings indicate a role for nitr ic oxide in methamphetamine-induced neurotoxicity and also suggest tha t blockade of NOS may be beneficial for the management of Parkinson's disease.