Effect of low doses of L-NAME on methamphetamine-induced dopaminergic depletion in the rat striatum.
The toxic dose of methamphetamine (METH) (5 mg/kg, s.c., x4, 2 hr intervals) decreased contents of dopamine, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in striatum, and decreased contents of serotonin (5-HT) in both striatum and nucleus accumbens. Administration of low doses of a non-selective endothelial and neuronal nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME) (5 and 10 mg/kg, i.p., x1) intensified the METH-induced decreases in contents of dopamine and its metabolites in striatum. NO substrate, L-arginine (500 mg/kg, i.p., x4) reversed these effects of L-NAME on the METH-neurotoxicity. L-NAME did not change the METH-induced hyperthermia. These findings, which are contrary to our previous study with a high dose of L-NAME, suggest that the inhibition of endothelial or neuronal NOS-mediated NO production by low doses of L-NAME enhanced the METH-induced neurotoxicity. The finding that L-NAME can have opposite effects on the METH-neurotoxicity according to the dosing is important, however, additional experiments should be performed to clarify which type of NOS is related to these effects.
Abekawa
T
T
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Nishi, Sapporo, Japan.
Ohmori
T
T
Honda
M
M
Ito
K
K
Koyama
T
T
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005334:Fever / Q000139:chemically induced / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D008694:Methamphetamine; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine