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 concentration-dependent, whereas the stimulation of dopamine outflow is seen only over a limited concentration range. M(1) and M(2) receptor stimulation has opposite effects on dopamine outflow. We postulated that the effect of SP on dopamine outflow depends on the M(1)/M(2) balance. We show that Ach (10-2500 microM) stimulates dopamine outflow in striatal slices in a biphasic manner, similar to SP (0.01-100 nM). An inactive SP concentration (10 nM) which was higher than the active concentration range, became active in the presence of the M(2) antagonist methoctramine (100 microM). Conversely, the effect of 1 nM SP was reversed by the M(1) antagonist pirenzepine (1 microM). Our observations show that SP modulation of dopamine outflow is determined by a balance between M(1) and M(2) receptors.
Khan
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Molecular Pharmacology Section, Division of Biomedical Sciences, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Mile End Road, E1 4NS, London, UK.
Whelpton
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R
Michael-Titus
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AT
D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003959:Diamines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D003959:Diamines; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013373:Substance P; D010890:Pirenzepine; D000109:Acetylcholine; C054938:methoctramine; D004298:Dopamine