Role of neuronal nitric oxide in methamphetamine neurotoxicity and protection by nNOS inhibitor

Methamphetamine (METH) is a potent psychostimulant known to produce neuroto xicity. The dopaminergic pathway is particularly sensitive to METH. Recent studies showed that 7-nitroindazole (7-NI), a selective inhibitor of neuron al nitric oxide synthase (nNOS), provided protection against METH neurotoxi city both in vitro and in vivo. The present studies were conducted to deter mine the nNOS activity in various regions of the brain of young adult male Sprague-Dawley rats treated with different doses of METH. Rats were injecte d ip with 5, 10, 20, and 40 mg/kg and 24 h after the rats were sacrificed a nd the brain regions (hippocampus, frontal cortex, and cerebellum) were qui ckly dissected. The cytosolic fractions were prepared, and the nNOS activit y was determined using the H-3-citrulline assay. The results showed that nN OS activity was significantly increased in all three brain regions of rats treated with METH. The increase was dose dependent reaching a maximum of 40 -100% over the control values. Rats treated with 7-NI 30 min prior to METH injection provided protection against the toxicity and also showed a reduct ion of nNOS activity. The activation of nNOS is known to increase the synth esis of NO which is involved in the regulation of several neurotransmitter pathways including catecholaminergic system. Reducing the METH-induced prod uction of NO by pretreatment with selective inhibitor of nNOS, 7-NI, provid ed protection against METH neurotoxicity.