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Vol. 284, Issue 3, 1040-1047, March 1998
Departments of
Biochemistry and Molecular Biology (Y.I.),
Microbiology and Immunology (C.G.), University of Miami School of
Medicine, Miami, Florida,
Cardiovascular Research Center, Department of
Medicine, Massachusetts General Hospital and Harvard Medical School
(P.L.H.), Charlestown, Massachusetts and
Neurochemistry Laboratory,
Division of Neurotoxicology (S.F.A.), National Center for Toxicological
Research, FDA, Jefferson, Arkansas
Methamphetamine (METH) is a powerful psychostimulant that produces
dopaminergic neurotoxicity manifested by a decrease in the levels of
dopamine, tyrosine hydroxylase activity and dopamine transporter (DAT)
binding sites in the nigrostriatal system. We have recently reported
that blockade of the neuronal nitric oxide synthase (nNOS) isoform by
7-nitroindazole provides protection against METH-induced neurotoxicity
in Swiss Webster mice. The present study was undertaken to investigate
the effect of a neurotoxic dose of METH on mutant mice lacking the nNOS
gene [nNOS(
/)] and wild-type controls. In addition, we sought to
investigate the behavioral outcome of exposure to a neurotoxic dose of
METH. Homozygote nNOS(/), heterozygote nNOS(+/) and wild-type
animals were administered either saline or METH (5 mg/kg × 3).
Dopamine, DOPAC and HVA levels, as well as DAT binding site levels,
were determined in striatal tissue derived 72 h after the last
METH injection. This regimen of METH given to nNOS(/) mice affected neither the tissue content of dopamine and its metabolites nor the
number of DAT binding sites. Although a moderate reduction in the
levels of dopamine (35%) and DAT binding sites (32%) occurred in
striatum of heterozygote nNOS(+/) mice, a more profound depletion of
the dopaminergic markers (up to 68%) was observed in the wild-type animals. METH-induced hyperthermia was observed in all animal strains
examined except the nNOS(/) mice. Investigation of the animals'
spontaneous locomotor activity before and after administration of the
neurotoxic dose of METH (5 mg/kg × 3) revealed no differences. A
low dose of METH (1.0 mg/kg) administered to naive animals (nNOS(/) and wild-type) resulted in a similar intensity of locomotor
stimulation. However, 68 to 72 h after exposure to the high-dose
METH regimen, a marked sensitized response to a challenge METH
injection was observed in the wild-type mice but not in the nNOS(/)
mice. Taken together, these results indicate that nNOS(/) mice are protected against METH-induced dopaminergic neurotoxicity and locomotor
sensitization. It also appears that a partial deficit of dopaminergic
transmission in wild-type animals does not prevent the development of
sensitization to METH, whereas a deficit in nNOS may attenuate this
process.
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