nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

Abstract

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.

• Authors: Y Itzhak, J L Martin, S F Ail
• Journal: Neuroreport (Neuroreport) Vol. 11 Issue 13 Pg. 2943-6 (Sep 11 2000) ISSN: 0959-4965 [Print] England
• PMID: 11006970 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 3-bromo-7-nitroindazole
• Enzyme Inhibitors
• Indazoles
• Neuroprotective Agents
• Neurotoxins
• Citrulline
• Nitric Oxide
• Methamphetamine
• Nitric Oxide Synthase
• Thiourea
• S-methylthiocitrulline
• 7-nitroindazole
• Dopamine

Topics

• Animals
• Citrulline (analogs & derivatives, pharmacology)
• Dopamine (metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions (physiology)
• Enzyme Inhibitors (pharmacology)
• Fever (chemically induced, metabolism, physiopathology)
• Indazoles (pharmacology)
• Male
• Methamphetamine (toxicity)
• Mice
• Neostriatum (cytology, drug effects, enzymology)
• Nerve Degeneration (chemically induced, metabolism, prevention & control)
• Neurons (cytology, drug effects, enzymology)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (toxicity)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Thiourea (analogs & derivatives, pharmacology)