win-51708 and 3-nitrotyrosine

In a previous study we showed that pharmacological blockade of the neurokinin-1 receptors attenuated the methamphetamine (METH)-induced toxicity of the striatal dopamine terminals. In the present study we examined the role of the neurokinin-1 receptors on the METH-induced apoptosis of some striatal neurons. To that end, we administered a single injection of METH (30 mg/kg, i.p.) to male mice. METH induced the apoptosis (terminal deoxyncleotidyl transferase-mediated dUTP nick end labeling) of approximately 20% of striatal neurons. This percentage of METH-induced apoptosis was significantly attenuated by either a single injection of the neurokinin-1 receptor antagonist, 17-beta-hydroxy-17-a-ethynyl-5-a-androstano[3,2-beta]pyrimido[1,2-a]benzimidazole (WIN-51,708) (5 mg/kg, i.p.), or the ablation of the striatal interneurons expressing the neurokinin-1 receptors (cholinergic and somatostatin) with the selective neurotoxin [Sar(9),Met(O(2))(11)] substance P-saporin. Next we assessed the levels of striatal 3-nitrotyrosine (3-NT) by HPLC and immunohistochemistry. METH increased the levels of striatal 3-NT and this increase was attenuated by pre-treatment with WIN-51,708. Our data support the hypothesis that METH-induced striatal apoptosis occurs via a mechanism involving the neurokinin-1 receptors and the activation of nitric oxide synthesis. Our findings are relevant for the treatment of METH abuse and may be relevant to certain neurological disorders involving the dopaminergic circuitry of the basal ganglia.

Topics: Analysis of Variance; Androstanes; Animals; Apoptosis; Benzimidazoles; Body Temperature; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Corpus Striatum; Dose-Response Relationship, Drug; Drug Combinations; Electrochemistry; Immunotoxins; In Situ Nick-End Labeling; Male; Methamphetamine; Mice; Mice, Inbred ICR; Microinjections; Nerve Tissue Proteins; Neurokinin-1 Receptor Antagonists; Nitric Oxide; Receptors, Neurokinin-1; Ribosome Inactivating Proteins, Type 1; Saporins; Substance P; Tyrosine