Effects of postnatal or adult chronic acetylcholinesterase inhibition on muscarinic receptors, phosphoinositide turnover and m1 mRNA expression.
Muscarinic receptor number, receptor-stimulated phosphoinositide hydrolysis and m1 mRNA expression were examined in the cerebral cortex and hippocampus of rats treated during postnatal development or in adult age with the organophosphate diisopropylfluorophosphate. Developing rats were treated from postnatal days 4-9 or from postnatal days 4-20 and killed on days 10 and 21, respectively, 24 h after the last administration of diisopropylfluorophosphate. Adult animals were treated for 14 days. Acetylcholinesterase activity and muscarinic receptor number were significantly reduced in all groups of treatment. Muscarinic receptor-stimulated phosphoinositide turnover, however, was significantly reduced in postnatal days 4-20 and adult treated rats but not in the postnatal days 4-9 group. No differences were observed in ED50 values. Conversely, m1 mRNA expression was significantly reduced both in the cerebral cortex and hippocampus of postnatal days 4-9 treated rats, but not of postnatal days 4-20 and adult treated rats. These results indicate that chronic inhibition of acetylcholinesterase in developing rats results in significant alterations in muscarinic neurotransmission. These alterations may delay the maturation of the cholinergic system and, therefore, may account for some of the long-lasting neurotoxic effects observed after developmental exposure to organophosphate pesticides.
Balduini
W
W
Institute of Pharmacology and Pharmacognosy, University of Urbino, Italy.
Cimino
M
M
Renò
F
F
Marini
P
P
Princivalle
A
A
Cattabeni
F
F
D000110:Acetylcholinesterase / Q000187:drug effects / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D017403:In Situ Hybridization; D007531:Isoflurophate / Q000633:toxicity*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D010716:Phosphatidylinositols; D012333:RNA, Messenger; D011976:Receptors, Muscarinic; D007531:Isoflurophate; D011813:Quinuclidinyl Benzilate; D000110:Acetylcholinesterase