Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition.
BACKGROUND
In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates.


OBJECTIVE
We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion.


RESULTS
Diazinon evoked up-regulation of 5HT1A and 5HT2 receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT1A receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects.


CONCLUSIONS
Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.
Slotkin
Theodore A
TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.slokin@duke.edu
Tate
Charlotte A
CA
Ryde
Ian T
IT
Levin
Edward D
ED
Seidler
Frederic J
FJ
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003976:Diazinon / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010278:Parathion / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D044348:Receptors, Serotonin, 5-HT2; D044282:Receptor, Serotonin, 5-HT1A; D010278:Parathion; D003976:Diazinon