Contrasting Effects of the Neuropeptides Substance P, Somatostatin, and Neuropeptide Y on the Methamphetamine-Induced Production of Striatal Nitric Oxide in Mice.

Several laboratories have shown that methamphetamine (METH) neurotoxicity is associated with increases of nitric oxide (NO) production in striatal tissue and blockade of NO production protects from METH. Because substance P modulates NO production, we tested the hypothesis that intrinsic striatal neuropeptides such as somatostatin and neuropeptide Y (NPY) modulate striatal NO production in the presence of METH. To that end, METH (30 mg/kg, IP) was injected into adult male mice alone or in combination with pharmacological agonists or antagonists of the neurokinin-1 (substance P), somatostatin or NPY receptors and 3-nitrotyrosine (an indirect index of NO production) was assessed utilizing HPLC or a histological method. Pre-treatment with the systemic neurokinin-1 receptor antagonist WIN-51,708 significantly attenuated the METH-induced production of striatal 3-NT measured at two hours post-METH. Conversely, intrastriatal injection of NPY1 or 2 receptor agonists inhibited the METH-induced production of striatal 3-NT. Similarly, intrastriatal infusion of the somatostatin receptor agonist octreotide attenuated the METH-induced striatal production of 3-NT. Taken together, our results suggest the hypothesis that the neuropeptide substance P is pro-damage while the neuropeptides somatostatin and NPY are anti-damage in the presence of METH by targeting the production of NO.