Effects of 7‐Nitroindazole, an NOS Inhibitor on Methamphetamine‐Induced Dopaminergic and Serotonergic Neurotoxicity in Micea

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Abstract
Methamphetamine (METH) is one of the major drugs of abuse that is postulated to cause neurotoxicity by depleting dopamine (DA) and its metabolites, high‐affinity DA uptake sites, and the activity of tyrosine hydroxylase. The present study was undertaken to investigate whether the relatively selective, neuronal nitric oxide synthase (NOS) inhibitor, 7‐nitroindazole (7‐NI), protects against METH‐induced neurotoxicity. Male Swiss Webster mice received the following injections intraperitoneally (i.p.) 3 times (every 3 hr): (i) vehicle/saline, (ii) 7‐NI (25 mg/kg)/saline, (iii) vehicle/METH (5 mg/kg), and (iv) 7‐NI (25 mg/kg)/METH (5 mg/kg). On the second day, groups (i) and (iii) received two vehicle injections and groups (ii) and (iv) received two 7‐NI injections (25 mg/kg each). The administration of vehicle/METH resulted in 68, 44 and 55% decreases in the concentration of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA), respectively, and a 48% decrease in the number of [3H]mazindol binding sites in the striatum compared to control values. The treatment with 7‐NI (group iv) provided a full protection against the depletion of DA and its metabolites, and the loss of dopamine transporter binding sites. Multiple injection of METH caused a significant decrease in the concentration of serotonin (5‐HT) and its metabolite 5‐hydroxyindole acetic acid (5‐HIAA). Treatment with 7‐NI partially blocked the depletion of 5‐HT and completely blocked the reduction in 5‐HIAA levels. The administration of 7‐NI/saline (group ii) affected neither the tissue concentration of DA, 5‐HT and their metabolites (DOPAC, HVA and 5‐HIAA) nor the binding parameters of [3H]‐mazindol compared to control (vehicle/saline) values. 7‐NI had no significant effect on the animals' body temperature, and it did not affect METH‐induced hyperthermia. These findings indicate a role for nitric oxide in METH‐induced neurotoxicity and also suggest that blockage of NOS may be beneficial for the management of Parkinson's disease.