Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice.
Previous studies have suggested a role for the retrograde messenger, nitric oxide (NO), in methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced dopaminergic neurotoxicity. Since evidence supported the involvement of the neuronal nitric oxide synthase (nNOS) isoform in the dopaminergic neurotoxicity, the present study was undertaken to investigate whether the inducible nitric oxide synthase (iNOS) isoform is also associated with METH- and MPTP-induced neurotoxicity. The administration of METH (5mg/kg x 3) to iNOS deficient mice [homozygote iNOS(-/-)] and wild type mice (C57BL/6) resulted in significantly smaller depletion of striatal dopaminergic markers in the iNOS(-/-) mice compared with the wild-type mice. METH-induced hyperthermia was also significantly lower in the iNOS(-/-) mice than in wild-type mice. In contrast to the outcome of METH administration, MPTP injections (20 mg/kg x 3) resulted in a similar decrease in striatal dopaminergic markers in iNOS(-/-) and wild-type mice. In the set of behavioral experiments, METH-induced locomotor sensitization was investigated. The acute administration of METH (1.0 mg/kg) resulted in the same intensity of locomotor activity in iNOS(-/-) and wild-type mice. Moreover, 68 to 72 h after the exposure to the high-dose METH regimen (5 mg/kg x 3), a marked sensitized response to a challenge injection of METH (1.0 mg/kg) was observed in both the iNOS(-/-) and wild-type mice. The finding that iNOS(-/-) mice were unprotected from MPTP-induced neurotoxicity suggests that the partial protection against METH-induced neurotoxicity observed was primarily associated with the diminished hyperthermic effect of METH seen in the iNOS(-/-) mice. Moreover, in contrast to nNOS deficiency, iNOS deficiency did not affect METH-induced behavioral sensitization.
Itzhak
Y
Y
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Miami, Florida 33136, USA. yitzhak@mednet.med.miami.edu
Martin
J L
JL
Ali
S F
SF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D005334:Fever / Q000139:chemically induced; D017353:Gene Deletion; D006719:Homovanillic Acid / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D008454:Mazindol / Q000378:metabolism; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D013997:Time Factors
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D008694:Methamphetamine; D008454:Mazindol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D004298:Dopamine; D006719:Homovanillic Acid