Functional alterations in CNS catecholamine systems in adolescence and adulthood after neonatal chlorpyrifos exposure.
Chlorpyrifos (CPF), one of the most widely used pesticides, is a neurobehavioral teratogen in animals. We administered CPF to neonatal rats on postnatal days (PN) 1-4 (1 mg/kg) or PN11-14 (5 mg/kg), regimens devoid of overt systemic toxicity. We then examined the impact on catecholaminergic systems in adolescence (PN30) and adulthood (PN60), assessing basal neurotransmitter content and transmitter utilization rates (turnover) in brain regions comprising the major noradrenergic and dopaminergic projections. Although CPF had only sporadic effects on basal norepinephrine and dopamine content, it profoundly suppressed norepinephrine turnover across multiple regions, indicative of net reductions in presynaptic activity. Dopamine turnover showed less consistent effects, with subnormal turnover in some regions and activation in others. We also evaluated whether CPF exposure altered the ability of catecholamine systems to respond to acute cholinergic stimulation, elicited by administration of a single challenge dose of nicotine. In the normal brain, nicotine increases the utilization of norepinephrine and dopamine. With only a few exceptions, animals receiving neonatal CPF exposure showed lasting desensitization of the nicotine response; not only was the activation by nicotine blunted in the CPF group, but in some regions the nicotine response was reversed, eliciting a reduction in transmitter turnover. These results indicate that neonatal CPF exposure produces widespread deficiencies in catecholaminergic synaptic function that persist into adulthood, and that are best revealed by dynamic measures of synaptic activity and responsiveness, as opposed to static markers like basal transmitter levels. The effects seen here are likely to contribute to alterations in behavioral performance that persist or emerge long after the termination of CPF exposure.
Slotkin
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TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA. t.slotkin@duke.edu
Tate
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CA
Cousins
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MM
Seidler
F J
FJ
D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D004390:Chlorpyrifos / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D009434:Neural Pathways / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity; D009538:Nicotine / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002395:Catecholamines; D007306:Insecticides; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D009538:Nicotine; D004390:Chlorpyrifos; D004298:Dopamine; D009638:Norepinephrine