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OtherNEUROPHARMACOLOGY

Resistance of Neuronal Nitric Oxide Synthase-Deficient Mice to Methamphetamine-Induced Dopaminergic Neurotoxicity

Yossef Itzhak, Carlos Gandia, Paul L. Huang and Syed F. Ali
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 1040-1047;
Yossef Itzhak
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Carlos Gandia
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Paul L. Huang
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Syed F. Ali
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Abstract

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.

Footnotes

  • Send reprint requests to: Yossef Itzhak, Ph.D., Department of Biochemistry and Molecular Biology (R-629), University of Miami School of Medicine, P.O. Box 016129, Miami, FL 33101.

  • ↵1 This study was supported by the National Institute on Drug Abuse (DA08584, to Y.I.) and by the National Institute of Neurological Disease and Stroke (NS33335, to P.L.H.).

  • Abbreviations:
    METH
    methamphetamine
    DAT
    dopamine transporter
    nNOS
    neuronal nitric oxide synthase
    NO
    nitric oxide
    DOPAC
    3,4-dihydroxyphenylacetic acid
    HVA
    homovanillic acid
    7-NI
    7-nitroindazole
    NMDA
    N-methyl-D-aspartate
    ANOVA
    analysis of variance
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    EAA
    exitatory amino acid
    • Received August 6, 1997.
    • Accepted November 17, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherNEUROPHARMACOLOGY

Resistance of Neuronal Nitric Oxide Synthase-Deficient Mice to Methamphetamine-Induced Dopaminergic Neurotoxicity

Yossef Itzhak, Carlos Gandia, Paul L. Huang and Syed F. Ali
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1040-1047;

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OtherNEUROPHARMACOLOGY

Resistance of Neuronal Nitric Oxide Synthase-Deficient Mice to Methamphetamine-Induced Dopaminergic Neurotoxicity

Yossef Itzhak, Carlos Gandia, Paul L. Huang and Syed F. Ali
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 1040-1047;
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