Heterogeneity of muscarinic autoreceptors and heteroreceptors in the rat brain: effects of a novel M1 agonist, AF102B.
The effects of oxotremorine and AF102B (cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine), a novel M1-selective muscarinic agonist, on acetylcholine (ACh) and dopamine (DA) release from superfused rat hippocampal and striatal synaptosomes were investigated. Synaptosomes that had been prelabeled with [3H]choline or [3H]DA were depolarized by high K+. Oxotremorine and AF102B decreased the K+-evoked [3H]ACh release from hippocampal synaptosomes and increased the K+-evoked [3H]DA release from striatal synaptosomes. The dose-response curves showed that AF102B was far less potent than oxotremorine at the hippocampal presynaptic muscarinic receptors (autoreceptors). On the other hand, AF102B was more potent than oxotremorine at the muscarinic receptors on the striatal dopaminergic terminals (heteroreceptors). Pirenzepine, a selective M1 antagonist, counteracted the effects of oxotremorine on [3H]DA release more potently than it did the effects of oxotremorine on [3H]ACh release. Our results suggest that AF102B and pirenzepine discriminate pharmacologically between muscarinic autoreceptors and heteroreceptors.
Ono
S
S
Research Institute of Life Science, Snow Brand Milk Products Co. Ltd., Tochigi, Japan.
Saito
Y
Y
Ohgane
N
N
Kawanishi
G
G
Mizobe
F
F
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D010095:Oxotremorine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D010890:Pirenzepine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes
D010277:Parasympathomimetics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013876:Thiophenes; D010890:Pirenzepine; D010095:Oxotremorine; C059240:cevimeline; D000109:Acetylcholine; D011188:Potassium; D004298:Dopamine