Abstract The roles of different dopamine receptors in mediating the responses of the striato-nigral substance P (SP) feedback loop were investigated. Subacute treatment of rats with the D 1 agonist, SK&F 38393, produced a significant decrease in SP content in the substantia nigra whereas treatment with the D 2 agonist, RU 24926, elevated nigral SP concentrations. Consequently, the elevation in nigral SP content which occurs following treatment with methamphetamine is likely a D 2-mediated event. This conclusion is supported by our observation that the D 2 antagonist, sulpiride, totally blocked the methamphetamine effect. These findings suggest that D 1 and D 2 receptors mediate opposing influences on the SP feedback system.