nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.
Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.
Itzhak
Y
Y
Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, FL 33136, USA.
Martin
J L
JL
Ail
S F
SF
D000818:Animals; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
C106731:3-bromo-7-nitroindazole; D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D002956:Citrulline; D009569:Nitric Oxide; D008694:Methamphetamine; D019001:Nitric Oxide Synthase; D013890:Thiourea; C086717:S-methylthiocitrulline; C080122:7-nitroindazole; D004298:Dopamine