Modulation of muscarinic receptors and acetylcholinesterase activity in lymphocytes and in brain areas following repeated organophosphate exposure in rats.
Repeated exposures to organophosphorus (OP) insecticides has been shown to cause a decrease of cholinergic muscarinic receptors (mAChR) in brain and in peripheral tissues. These changes are believed to be involved in the development of tolerance to OP toxicity and may play a role in cognitive dysfunctions observed following repeated OP exposure. Recently, mAChRs identified in circulating lymphocytes have been shown to be modulated similarly to brain mAChRs following repeated OP exposure, suggesting that these peripheral cells may be useful as indicators of mAChR changes in the central nervous system. This study was designed to further investigate whether mAChRs on lymphocytes could serve as a biomarker for changes in brain mAChRs during prolonged OP exposure and during recovery from such exposure. Using the mAChR antagonist [3H]quinuclidinyl benzilate (QNB) to label mAChRs, we found that exposure to disulfoton for 14 days (2 mg/kg/day by gavage) caused a significant decrease (25-35%) in muscarinic receptors density in the cerebral cortex, hippocampus, and striatum, as well as in circulating lymphocytes. The decline of mAChR density in lymphocytes paralleled those observed in brain, particularly in cortex and hippocampus, during exposure to disulfoton; however, while brain mAChR levels recovered slowly after termination of exposure and remained significantly reduced 4 weeks after the last treatment, [3H]QNB binding in lymphocytes recovered rapidly within 1 week. Similarly, lymphocyte acetylcholinesterase (AChE) activity was significantly inhibited and correlated well with brain AChE activity during exposure, but the recovery was rapid relative to AChE activity in brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Fitzgerald
B B
BB
Department of Environmental Health, University of Washington, Seattle 98105.
Costa
L G
LG
D000110:Acetylcholinesterase / Q000097:blood* / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004222:Disulfoton / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure*; D014316:Tritium
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D011976:Receptors, Muscarinic; D014316:Tritium; D004222:Disulfoton; D011813:Quinuclidinyl Benzilate; D000110:Acetylcholinesterase