Substance P fragments and striatal endogenous dopamine outflow: interaction with substance P

Accumulating evidence shows that N- and C-terminal substance P fragments ha ve significant biological activity. Substance P(1-9) and substance P(6-11) have been reported to be major substance P metabolites in rat striatum. We investigated the effects of these fragments on endogenous dopamine outflow in rat striatal slices. Substance P-(1-9) and substance P-(6-11) induced a significant increase in dopamine outflow at 0.1 and 1 nM, The effects of su bstance P-(6-11) (1 nM) were reversed by the tachykinin NK1 antagonist WIN 51,708 (17 beta-hydroxy-17 alpha-ethynyl-5 alpha-androstano[3,2-b]pyrimido[ 1,2-a]benzimidazole) (2.5 nM), whereas the effects of substance P-(1-9) wer e not modified by the antagonist. Substance P-(1-9) and substance P-(6-11) (1 nM) did not increase the dopamine overflow induced by 25 mM KCI. The eff ects of the two fragments were reversed by the muscarinic antagonist atropi ne (1 1 mu M) but not by nicotinic antagonists dihydro-beta-erythroidine (0 .5 mu M) and pempidine (10 mu M). The co-incubation of tissue with substanc e P and each fragment in a 1/1 or 10/1 ratio of substance P to metabolite r evealed a negative interaction between parent and fragments. A similar patt ern was observed when substance P was co-administered with the active fragm ents substance P(1-4), substance P(1-7), substance P(5-11) and substance P( 8-11), The data show that substance P-(1-9) and substance P-(6-11) have mod ulatory effects similar to substance P. However, the presence of active sub stance P metabolites does not appear to amplify the signal mediated by the parent peptide.