Differential effects of M1- and M2-muscarinic drugs on striatal dopamine release and metabolism in freely moving rats.
A dialysis loop cannula was implanted into rat striatum under anesthetized condition, and the area was perfused with Ringer's solution under freely moving condition after 3 days for surgical recovery. Dopamine (DA) and 3,4-dihydroxyphenylacetic acid recovered in the dialysate were measured by high-performance liquid chromatography with electrochemical detection. The effects of M1- and M2-muscarinic receptor agents, which were perfused continuously into the striatum through the dialysis membrane, were investigated. Continuous perfusion of AF102B, an M1-selective agonist, and oxotremorine, a non-selective agonist, resulted in a dose-dependent increase in the striatal DA release. Pirenzepine (10(-5) and 10(-7) M), an M1-selective antagonist, decreased the release of DA, and the stimulatory effect of AF102B (10(-5) M) was completely inhibited by 10(-5) and 10(-7) M pirenzepine, while the stimulatory effect of oxotremorine (10(-4) M) was only partly inhibited by 10(-5) M pirenzepine. AF-DX116 (10(-5) M), an M2-selective antagonist, increased the DA release, and showed an additive effect on the DA release evoked by AF102B (10(-5) M), whereas it produced no significant effect on oxotremorine (10(-5) M)-evoked DA release. These results suggest that in vivo DA release in the rat striatum is modulated by different subtypes of muscarinic receptors; i.e., the stimulatory effect is mainly mediated by M1-sites and inhibitory effect is mainly mediated by M2-sites. The changes in the DA release induced by the various drugs were prevented by pretreatment with tetrodotoxin (TTX). Since action potential-dependent DA release (exocytosis) is blocked by the pretreatment with TTX, those drugs affect DA release by means of action potential-dependent processes.
Department of Life Chemistry, Graduate School at Nagatsuta, Tokyo Institute of Technology, Yokohama, Japan.
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Xu
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Mizobe
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Yamamoto
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Kato
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010095:Oxotremorine / Q000008:administration & dosage / Q000494:pharmacology*; D010890:Pirenzepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011812:Quinuclidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013876:Thiophenes
D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013876:Thiophenes; D010890:Pirenzepine; D010095:Oxotremorine; C059240:cevimeline; C048593:otenzepad; D004298:Dopamine