Substance P modulation of striatal dopamine outflow is determined by M-1 and M-2 muscarinic receptors in male Wistar rats

Substance P (SP) stimulates striatal dopamine outflow through a cholinergic muscarinic link. SP-induced increase in acetylcholine,(Ach) is concentrati on-dependent, whereas the stimulation of dopamine outflow is seen only over a limited concentration range. M-1 and M-2 receptor stimulation has opposi te effects on dopamine outflow. We postulated that the effect of SP on dopa mine outflow depends on the M-1/M-2 balance. We show that Ach (10-2500 muM) stimulates dopamine outflow in striatal slices in a biphasic manner, simil ar to SP (0.01-100 nM).An inactive SP concentration (10 nM) which was highe r than the active concentration range, became active in the presence of the M-2 antagonist methoctramine (100 muM). Conversely, the effect of 1 nM SP was reversed by the M-1 antagonist pirenzepine (1 muM). Our observations sh ow that SP modulation of dopamine outflow is determined by a balance betwee n M1 and M2 receptors. (C) 2000 Elsevier Science Ireland Ltd. All rights re served.