Effects of diisopropyl fluorophosphate on muscarinic-M1-receptors and on receptor-mediated responsiveness of the phosphatidyl-inositol system in the cerebral cortex of rats.
The effects of acute and repeated treatments with an anticholinesterase (anti-ChE) compound, diisopropylfluorophosphate (DFP) on M1-acetylcholine receptor (M1-AChRs) density and on M1-mediated breakdown of inositol phospholipids were studied in the cerebral cortex of rats. The DFP doses induced an about 75% inhibition of cortical ChE 48 hr after the last treatment. The acute treatment did not change Bmax of M1-AChRs (measured as 3H-pirenzepine binding), while 1-week and 2-weeks treatments induced their significant down-regulation, by 14 and 29%, respectively. The responsiveness of M1-AChRs was measured in cortical prisms as accumulation of inositol phosphate (IP) following stimulation with a cholinergic agonist, carbachol (from 10 to 1000 microM). The IP accumulation (expressed as ratio stimulated/basal IP content) was lower in acute DFP rats than in controls at few carbachol concentrations, and after 2 weeks at most carbachol concentrations. This resulted in a significant increase of EC50. The data indicate the involvement of cortical phosphatidyl inositol system during intoxication by anti-ChE agents, namely a decreased efficiency of post-receptor mechanisms.
Pintor
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A
Laboratory of Pharmacology, Istituto Superiore di Sanità, Rome, Italy.
Fortuna
S
S
Nalepa
I
I
Michalek
H
H
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002802:Cholinesterases / Q000378:metabolism; D006868:Hydrolysis; D007531:Isoflurophate / Q000494:pharmacology*; D008297:Male; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*
D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D007531:Isoflurophate; D002802:Cholinesterases