cGMP formation and phosphoinositide turnover in rat brain slices are mediated by pharmacologically distinct muscarinic acetylcholine receptors.
The cGMP response and the accumulation of inositol monophosphate (IP) induced by carbachol were compared in slices of different rat brain structures. Basal cGMP and the responses of cGMP to carbachol appeared dependent on the concentration of added Ca2+, suggesting that distinct Ca(2+)-mediated and Ca(2+)-sensitive muscarinic receptor-mediated mechanisms stimulate guanylate cyclase. Regional responses of cGMP to carbachol or to direct stimulation of guanylate cyclase with sodium nitroprusside were markedly distinct, indicating that a major proportion of guanylate cyclase in the cortex, an intermediate proportion in other forebrain regions, and only a minor proportion in the brainstem is sensitive to muscarinic receptor stimulation. The regional patterns of IP and cGMP responses to carbachol were different in the forebrain. Maximal IP accumulation was found in the cortex, whereas cGMP responses were highest in the hippocampus. Moreover, IP and cGMP formation in the hippocampus were differently antagonized by atropine, 4-diphenylacetoxy-N-methyl piperidine methiodide (4-DAMP), the M2-receptor subtype-preferring antagonist AF-DX 116 and the M1-selective antagonist pirenzepine. These data support the notion that the IP formation induced by carbachol in the forebrain predominantly is mediated by muscarinic receptors of the M1 subtype, and indicate the involvement of muscarinic receptors of the M3 subtype in the carbachol-induced cGMP formation.
CNS Pharmacology Department, Organon International, Oss, The Netherlands.
J A
JA
Tonnaer
C L
CL
Cheung
T
T
De Boer
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology*; D006152:Cyclic GMP / Q000096:biosynthesis* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013388:Succinimides / Q000494:pharmacology
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D010880:Piperidines; D011976:Receptors, Muscarinic; D013388:Succinimides; D009599:Nitroprusside; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D001285:Atropine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; D006162:Guanylate Cyclase; D006152:Cyclic GMP