BLOCKADE OF TACHYKININ NK(1) RECEPTORS BY CP-96345 ENHANCES DOPAMINE RELEASE AND THE STRIATAL DOPAMINE EFFECTS OF METHAMPHETAMINE IN RATS

The nonpeptide, tachykinin NK1 receptor antagonist, CP-96345, permits the study of the physiological role of extrapyramidal substance P systems. Using microdialysis, we observed that locally applied CP-96345 (200 nM) caused a significant increase in dopamine release in the striatum as well as substantially enhancing striatal dopamine releaSe Caused by a low dose of methamphetamine (0.5 mg/kg s.c.). In addition, multiple systemic administrations of CP-96345 almost doubled the dopamine-mediated responses of the striatal neurotensin and dynorphin systems to high doses of methamphetamine ( 10 mg/kg/dose s.c.). Our findings suggest that the physiological role of substance P released in the striatum is to decrease the activity of the nigrostriatal dopamine pathway.