PRESYNAPTIC MODULATION OF ANTICHOLINESTERASE TOXICITY

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DESCRIPTION: (Adapted from the Investigator's Abstract) Organophosphorus insecticides (OPs) exert toxicity through inhibition of acetylcholinesterase, allowing accumulation of acetylcholine and excessive stimulation of postsynaptic cholinergic receptors. Considerable age-related differences in sensitivity to these agents are evident. We hypothesize that presynaptic modulation of anticholinesterase toxicity can occur through alterations in the synthesis and/or release of acetylcholine and that age-related differences in sensitivity are, along with differences in biotransformation and postsynaptic receptor adaptations, due to the relative activity or adaptability of these presynaptic processes. Acute sensitivity to the most common OP in use today, chlorpyrifos, will be compared to the prototype OP, parathion, in neonatal, juvenile, young adult and aged rats. Age-related differences in the A-esterase- and carboxylesterase-meditated detoxification of the oxons will be correlated with differences in acute sensitivity. Acetylcholine synthesis will be assayed by measuring high-affinity choline uptake, the rate-limiting step. Modulatory effects of in vivo OP exposure on high-affinity choline uptake in the different age groups will be examined and compared to changes in other neurochemical markers (acetylcholinesterase, muscarinic and nicotinic receptor binding). Acetylcholine release and its presynaptic autoreceptor-mediated modulation will be studied using brain slices (muscarinic autoreceptor) or synaptosomes (nicotinic autoreceptor), [3H]choline preloading and potassium-evoked release in a superfusion system. Autoreceptor regulation of acetylcholine release ex vivo following OP exposure will be compared in the different age groups and correlated with acute OP sensitivity. Finally, comparative age-related effects of OP exposures on the muscarinic receptor-mediated cAMP cascade and phosphoinositide turnover systems will be examined. These studies should define the relative activity and compensatory nature of presynaptic cholinergic mechanisms during maturation and aging and determine the effects of their modulation on OP sensitivity.