Nitric oxide and the neurotoxic effects of methamphetamine and 3,4-methylenedioxymethamphetamine.
The role of nitric oxide (NO) in the long-term, amine-depleting effects of methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) was investigated in the rodent central nervous system. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) antagonized the dopamine- and serotonin-depleting effects of both METH and MDMA. The protective actions of L-NAME in METH-treated mice were reversed by prior administration of the NO generator isosorbide dinitrate. However, pretreatment with N(G)-monomethyl-L-arginine or N(G)-nitro-L-arginine, two other NO synthase inhibitors, failed to block the neurotoxic effects of METH or MDMA. L-NAME was also the only NO synthase inhibitor that antagonized the hyperthermic effects of METH, reducing colonic temperatures in mice by a mean of 3 degrees C, in comparison with control. Moreover, if the hypothermic effects of L-NAME in METH-treated mice were prevented by raising the ambient room temperature, the dopamine-depleting actions of the stimulant were fully restored. The latter findings suggest that it is the hypothermic actions of L-NAME, rather than its NO inhibitory properties, that are responsible for the prevention of neurotoxicity. Together with the results of the N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine experiments, the data suggest that NO plays little or no role in the toxic mechanism of action of METH or MDMA.
Taraska
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Department of Psychiatry, University of Utah School of Medicine, Veterans Administration Medical Center, Salt Lake City 84148, USA.
Finnegan
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KT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009498:Neurotoxins; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*
D002395:Catecholamines; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D019335:Nitroarginine; D009569:Nitric Oxide; D012701:Serotonin; D008694:Methamphetamine; D006897:Hydroxyindoleacetic Acid; D019001:Nitric Oxide Synthase; D007548:Isosorbide Dinitrate; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine; D006719:Homovanillic Acid