Nitric oxide is implicated in methamphetamine-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work also demonstrates that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later. The current study examined nitric oxide synthase expression and activity, and protein nitrosylation in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on PND90 (Saline:METH and METH:METH) increased nitric oxide production as evidenced by increased protein nitrosylation. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change in the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of nNOS mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production following a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity rather than an induction of mRNA and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide following methamphetamine administration. Interestingly, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury.
- Received September 7, 2012.
- Revision received November 21, 2012.
- Accepted December 7, 2012.
- The American Society for Pharmacology and Experimental Therapeutics