CHLORPYRIFOS OXON BINDS DIRECTLY TO MUSCARINIC RECEPTORS AND INHIBITSCAMP ACCUMULATION IN RAT STRIATUM

Although the acute effects of organophosphorus esters are generally as cribed to inhibition of acetylcholinesterase, work in this laboratory and others indicates that organophosphorus insecticides also interact directly with cholinergic receptors. The current study verifies that t he insecticide O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothio ate (chlorpyrifos) and its oxon metabolite inhibits acetylcholinestera se (AChE). The metabolite inhibits rat brain AChE three orders of magn itude more rapidly than chlorpyrifos. In addition to their ability to inhibit AChE, these compounds were shown to interact directly with mus carinic receptors of rat striatum. The oxon metabolite bound at low co ncentrations to muscarinic receptors labeled by the muscarinic agonist [H-3]cis-methyldioxolane; chlorpyrifos oxon bound with an IC50 value of 22.1 +/- 3.6 nM. The receptors bound by chlorpyrifos oxon account f or approximately 30% of muscarinic receptors of the striatum and are o f the m2 subtype. The binding of chlorpyrifos oxon to the m2 receptor results in a covalent modification of the receptor that does not inter fere with the ability of the receptor to interact with the agonist car bachol. This receptor modification may be responsible for the inhibiti on of adenylate cyclase activity by chlorpyrifos oxon. The oxon inhibi ted adenylate cyclase with an IC50 of 155 +/- 78 nM. The inhibition of adenylate cyclase activity was not blocked by atropine and was additi ve to that produced by carbachol. The altering of postreceptor signal transduction by chlorpyrifos oxon may interfere with normal cellular s ignaling, thereby disturbing neurological function. Direct interaction of chlorpyrifos oxon with muscarinic receptors and associated signal transduction is a potential mechanism of neurotoxicity that is indepen dent of AChE inhibition.