SUBSTANCE P-(1-7) AND SUBSTANCE P-(5-11) LOCALLY MODULATE DOPAMINE RELEASE IN RAT STRIATUM

The effects of substance P, substance P-(1-7) and substance P-(5-11) o n endogenous dopamine outflow in rat striatal slices were investigated . The dose-response curves (0.01 nM to 10 mu M) were bell-shaped, with significant increases at 0.1 and 1 nM but with no effect at higher co ncentrations. The tachykinin NK1 receptor agonist, [Sar(9),Met(O-2)(11 )] substance P, significantly increased dopamine outflow at 10 and 100 nM. The effects of substance P or substance P-(5-ll) and 25 mM KCl we re additive. A negative interaction was observed with substance P-(1-7 ) and K+. The increase in dopamine outflow elicited by 1 nM substance P and substance P-(5-11) was reversed by the tachykinin NK1 receptor a ntagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androst ano[3,2-b ]pyrimido[1,2-a]benzimidazole) (25 and 250 nM), whereas only partial reversal was observed for the effect of substance P-(1-7). Th ese results show that substance P fragments locally modulate striatal dopamine outflow and the mechanisms underlying this modulation may dif fer between N-and C-terminal fragments.