ROLE OF NITRIC-OXIDE IN METHAMPHETAMINE NEUROTOXICITY - PROTECTION BY7-NITROINDAZOLE, AN INHIBITOR OF NEURONAL NITRIC-OXIDE SYNTHASE

The role of nitric oxide (NO.) in the neurotoxic effects of methamphet amine (METH) was evaluated using 7-nitroindazole (7-NI), a potent inhi bitor of neuronal nitric oxide synthase, Treatment of mice with 7-NI ( 50 mg/kg) almost completely counteracted the loss of dopamine, 3,4-dih ydroxyphenylacetic acid, and tyrosine hydroxylase immunoreactivity obs erved 5 days after four injections of 10 or 7.5 mg/kg METH. With the h igher dose of METH, this protection at 5 days occurred despite the fac t that combined administration of METH and 7-NI significantly increase d lethality and exacerbated METH-induced dopamine release (as indicate d by a greater dopamine depletion at 90 min and 1 day). Combined treat ment with 4 x 10 mg/kg METH and 7-NI also slightly increased the body temperature of mice as compared with METH alone. Thus, the neuroprotec tive effects of 7-NI are independent from lethality, are not likely to be related to a reduction of METH-induced dopamine release, and are n ot due to a decrease in body temperature. These results indicate that NO. formation is an important step leading to METH neurotoxicity, and suggest that the cytotoxic properties of NO. may be directly involved in dopaminergic terminal damage.