Research ReportSynergism between methamphetamine and the neuropeptide substance P on the production of nitric oxide in the striatum of mice

Our laboratory has been investigating the participation of striatal neurokinin-1 receptors in the methamphetamine (METH)-induced loss of striatal neurons. Signaling through these receptors exacerbates the METH-induced striatal apoptosis. METH induces the synthesis of nitric oxide (NO) and the latter has been linked to the activation of neurodegenerative cascades. In the present study, we assessed the role of the neurokinin-1 receptor in the production of striatal 3-nitrotyrosine (3-NT) and l-citrulline (indirect indices of NO production). To that end, we injected male mice with a bolus of METH (30 mg/kg, ip) and visualized striatal neuronal nitric oxide synthase (NOS)-positive cells by immunohistochemistry and protein levels by Western blot. The expression of neuronal NOS or protein levels at 2, 4 and 8 hours post-METH was unchanged. Next, we assessed 3-NT and l-citrulline by immunohistochemistry. At 4 hours post-METH, striatal 3-NT and l-citrulline levels were increased 30- and 5-fold, respectively, relative to controls and the selective neurokinin-1 receptor antagonist WIN-51,708 attenuated these increases. Intrastriatal infusion of the neurokinin-1 receptor agonist GR-73632 induced striatal 3-NT production that was attenuated with systemic injection of WIN-51,708 or 7-nitroindazole (7-NI, an inhibitor of neuronal NOS). Moreover, infusion of calmidazolium (calmodulin inhibitor) with GR-73632 prevented the production of 3-NT. These data are consistent with the hypothesis that METH-induced production of NO is modulated by the striatal neurokinin-1 receptors and that this receptor may participate in the biochemical activation of neuronal NOS.

Research Highlights►Methamphetamine activates striatal nitric oxide synthesis. ►Substance P modulates nitric oxide synthesis in the presence of methamphetamine. ►Activation of the striatal neurokinin-1 receptor induces nitric oxide production.