Abstract
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 withN G-monomethyl-l-arginine orN 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°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 theN G-monomethyl-l-arginine andN 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.
Footnotes
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Send reprint requests to: Kevin T. Finnegan, M.D., Ph.D., Psychiatry Service (116A), Veterans Administration Medical Center, 500 Foothill Blvd., Salt Lake City, UT 84148.
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↵1 This work was supported in part by grants from the Office of Veterans Affairs and the National Institute on Drug Abuse (DA07239).
- Abbreviations:
- CNS
- central nervous system
- DA
- dopamine
- 5-HT
- 5-hydroxytryptamine
- MDMA
- 3,4-methylenedioxymethamphetamine
- METH
- methamphetamine
- l-NAME
- N G-nitro-l-arginine methyl ester
- NMDA
- N-methyl-d-aspartate
- NO
- nitric oxide
- NOS
- nitric oxide synthase
- Received May 10, 1996.
- Accepted October 21, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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