Effects of sub-chronic in vivo chlorpyrifos exposure on muscarinic receptors and adenylate cyclase of rat striatum.
In this study dosing regimens were designed such that cholinesterase inhibition following exposure to chlorpyrifos was produced in one treatment group, but was absent in the other. The higher dosing regimen inhibited plasma and brain cholinesterase activities by 51 and 70%, respectively, and resulted in decreased [3H]cis-methyldioxolane ([3H]CD) binding, which was attributable to a decrease in Bmax. No concomitant loss of [3H]quinuclidinyl benzilate ([3H]QNB) binding sites was observed, indicating that the M2 muscarinic receptor subtype to which [3H]CD binds is particularly susceptible to alterations induced by chlorpyrifos treatment. As the M2 receptor subtype is surmised to be the muscarinic autoreceptor, decreases in this receptor may exacerbate poisoning by organophosphorus agents as a result of decreased ability to terminate synaptic acetylcholine release. The ability of carbachol to inhibit striatal adenylate cyclase, which is an effector molecule associated with the M2 receptor, was unaltered in chlorpyrifos-treated rats. Decreases in M2 receptors occurred with the higher dosing regimen, in the absence of any clinical manifestations. Thus, in the absence of overt clinical signs, perturbations of the muscarinic receptor system did occur as a result of sub-chronic chlorpyrifos exposure. Such alterations may contribute to neurological impairments that develop following chronic organophosphorus exposure.
Huff
R A
RA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Abu-Qare
A W
AW
Abou-Donia
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MB
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D004390:Chlorpyrifos / Q000633:toxicity*; D018678:Cholinergic Agents / Q000378:metabolism; D002802:Cholinesterases / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007279:Injections, Subcutaneous; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D018678:Cholinergic Agents; D004791:Enzyme Inhibitors; D007306:Insecticides; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D002802:Cholinesterases; D004390:Chlorpyrifos