N-TERMINAL AND C-TERMINAL SUBSTANCE-P FRAGMENTS MODULATE STRIATAL DOPAMINE OUTFLOW THROUGH A CHOLINERGIC LINK MEDIATED BY MUSCARINIC RECEPTORS

The present study investigated whether the modulatory effects of subst ance P and substance P fragments on striatal dopamine release involve a cholinergic link. Rat striatal slices were incubated with substance P, substance P(1-4), substance P(1-7), substance P(5-11) and substance P(8-11) in the absence or presence of various agents which modify cho linergic transmissions, and endogenous dopamine outflow was measured u sing high-performance liquid chromatography. The incubation of striata l slices with substance P and its N- and C-terminal fragments (1 nM) i nduced a significant overflow of endogenous dopamine. Neostigmine (150 nM) potentiated the effects of substance P and its fragments, whereas the incubation with hemicholinium-3 (50 mu M) abolished the effects o f the peptides on dopamine outflow. The acetylcholinesterase inhibitor and the inhibitor of choline uptake did not have intrinsic effects on dopamine outflow. The muscarinic antagonist atropine (1 mu M) reverse d completely the effects of substance P and its fragments, whereas the nicotinic antagonists dihydro-beta-erythroidine (0.5 mu M) and pempid ine (10 mu M) were devoid of effects. None of the cholinergic antagoni sts modified dopamine outflow. The results suggest that substance P an d several N- and C-terminal substance P fragments activate cholinergic neurons in striatal slices. The released acetylcholine induces an inc reased dopamine outflow, mediated by muscarinic receptors. These obser vations represent additional evidence which supports the functional in teractions between substance P, acetylcholine and dopamine in the stri atum. Furthermore, they show that substance P fragments may exert neur omodulatory effects through mechanisms similar to those underlying the effects of the parent peptide. Copyright (C) 1966 IBRO.