Investigations of amitraz neurotoxicity in rats. III. Effects on motor activity and inhibition of monoamine oxidase.
The formamidine pesticide amitraz (AMZ) produces many behavioral and physiological changes in rats. We examined the dose effect and time course of AMZ on motor activity, monoamine oxidase (MAO) activity, and acetylcholinesterase (AChE) activity to evaluate possible neurochemical mechanisms for the behavioral effects of AMZ. For motor activity studies, male Long-Evans hooded rats were tested in photocell activity measurement devices. AMZ produced dose-related decreases in motor activity of rats allowed free access to food and rats maintained at a stable body weight through food restriction. Lowest effective doses of AMZ tested were 1-3 mg/kg, administered 20 min before testing. AMZ appeared to be about three times more potent in food-restricted rats, indicating that amount of body fat may play a significant role in the pharmacokinetics of AMZ. Motor activity returned to control levels over 4-5 days after dosing with 100-200 mg/kg AMZ, whereas recovery was evident the day after administration of low doses (1-30 mg/kg). Inhibition of MAO was measured in whole brain of rats sacrificed at various times after dosing with AMZ. Only greater than or equal to 100 mg/kg AMZ inhibited MAO, which was measurable within 2 hr of dosing and lasted up to 7 days. AMZ appeared to be more selective for type B MAO when given in vivo, although MAO-A was also inhibited at doses greater than or equal to 300 mg/kg. However, no selectivity was indicated by the IC50 values determined in vitro (IC50 = 31 and 28 microM for MAO-A and MAO-B, respectively). AMZ produced only negligible inhibition of AChE at the highest doses administered in vivo or at 10 mM in vitro. These data indicate that while AMZ does inhibit MAO, the dose range over which it produces this action is much higher than that which suppressed motor activity. Thus MAO inhibition is probably not responsible for AMZ-induced alterations in motor activity.
Moser
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Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
MacPhail
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007302:Insect Repellents / Q000633:toxicity*; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects*; D009420:Nervous System / Q000187:drug effects*; D051381:Rats; D014052:Toluidines / Q000633:toxicity*
D007302:Insect Repellents; D008996:Monoamine Oxidase Inhibitors; D014052:Toluidines; C014983:amitraz