Resistance of neuronal nitrix oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity

Yossef Itzhak, Carlos Gandia, Paul L. Huang, 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 x 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 x 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 the 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.

Original languageEnglish
Pages (from-to)1040-1047
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume284
Issue number3
StatePublished - Mar 1 1998

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Methamphetamine
Nitric Oxide Synthase Type I
Oxides
Dopamine Plasma Membrane Transport Proteins
Wild Animals
Dopamine
Binding Sites
Heterozygote
L-arginine alpha-ketoglutarate
Corpus Striatum
3,4-Dihydroxyphenylacetic Acid
Induced Hyperthermia
Injections
Homozygote
Tyrosine 3-Monooxygenase
Locomotion
Protein Isoforms

ASJC Scopus subject areas

  • Pharmacology

Cite this

Resistance of neuronal nitrix oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity. / Itzhak, Yossef; Gandia, Carlos; Huang, Paul L.; Ali, Syed F.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 284, No. 3, 01.03.1998, p. 1040-1047.

Research output: Contribution to journalArticle

Itzhak, Yossef ; Gandia, Carlos ; Huang, Paul L. ; Ali, Syed F. / Resistance of neuronal nitrix oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity. In: Journal of Pharmacology and Experimental Therapeutics. 1998 ; Vol. 284, No. 3. pp. 1040-1047.
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