Role of neuronal nitric oxide in methamphetamine neurotoxicity and
protection by nNOS inhibitor*
D. Desaiah1*, S. L. N. Reddy1,
S. Z. Imam2, and S. F. Ali2
1Department of Neurology,
University of Mississippi Medical Center, Jackson, MS 39216, USA
2Division
of Neurotoxicology, National Center for Toxicological Research, Jefferson,
AR 72079, USA
Abstract: Methamphetamine (METH) is a potent psychostimulant
known to produce neurotoxicity. The dopaminergic pathway is particularly
sensitive to METH. Recent studies showed that 7-nitroindazole (7-NI),
a selective inhibitor of neuronal nitric oxide synthase (nNOS), provided
protection against METH neurotoxicity both in vitro and in
vivo. The present studies were conducted to determine the nNOS activity
in various regions of the brain of young adult male Sprague-Dawley rats
treated with different doses of METH. Rats were injected ip with 5,
10, 20, and 40 mg/kg and 24 h after the rats were sacrificed and the
brain regions (hippocampus, frontal cortex, and cerebellum) were quickly
dissected. The cytosolic fractions were prepared, and the nNOS activity
was determined using the 3H-citrulline assay. The results
showed that nNOS 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 7NI
30 min prior to METH injection provided protection against the toxicity
and also showed a reduction of nNOS activity. The activation of nNOS
is known to increase the synthesis of NO which is involved in the regulation
of several neurotransmitter pathways including catecholaminergic system.
Reducing the METH-induced production of NO by pretreatment with selective
inhibitor of nNOS, 7-NI, provided protection against METH neurotoxicity.
*Lectures presented
at the 4th Congress of Toxicology in Developing Countries (4th CTOX-DC),
Antalya, Turkey, 6-10 November 1999
**Corresponding author
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