Vol. 280, Issue 2, 941-947, 1997

Nitric Oxide and the Neurotoxic Effects of Methamphetamine and 3,4-Methylenedioxymethamphetamine¹

Terri Taraska and Kevin T. Finnegan

Departments of Psychiatry (T.T., K.T.F.), Pharmacology and Toxicology (K.T.F.) and Neuroscience (K.T.F.), University of Utah School of Medicine and the Veterans Administration Medical Center, Salt Lake City, Utah

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°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.