No changes in behaviour, nigro-striatal system neurochemistry or neuronal cell death following toxic multiple oral paraquat administration to rats.
We have examined whether the widely used herbicide, paraquat (1,1'-dimethyl-4,4'dipyridylium) may accumulate in rat brain following multiple oral dosing (5 mg paraquat ion/kg/day) for 14 days and whether this dosing regime may produce signs of neurotoxicity. This dosing regime may determine whether low dose exposure to mammals may be neurotoxic. Using [14C]paraquat to measure tissue and plasma paraquat concentrations, we observed significantly higher plasma and tissue paraquat concentrations in brain, liver, lungs and kidneys of rats which received multiple doses for 14 days, as compared to paraquat concentrations in tissues of rats which received only a single paraquat dose. Brain paraquat concentrations measured 24 h after dosing were tenfold higher in rats receiving 14 daily oral doses of paraquat, as compared to concentrations following a single oral dose. A neuropathological study of the rat brain yielded no evidence that multiple paraquat dosing resulted in neuronal cell damage. Particular attention was paid to the nigrostriatal system. The paraquat treated rats gained approximately 10% less body weight over the 15 day experimental period as compared with controls demonstrating that the dose of paraquat was toxic to the animals. Measurements of locomotor activity using open field tests or activity monitors did not reveal any statistically significant differences between control animals and those receiving paraquat. Fore- and hind-limb grip strength were not significantly different between the paraquat treated and control rats at any time point during the dosing regime, nor was there any evidence for locomotor coordination deficits in any of the animals receiving paraquat. Densities of dopamine D1 and D2, NMDA, muscarinic and benzodiazepine receptors in the cerebral cortex and striatum were not significantly different between controls and rats which had received multiple paraquat doses. Concentrations of catecholamine neurotransmitters in the striatum, hypothalamus and frontal cerebral cortex were also measured to examine whether there was evidence for catecholamine depletion in these brain regions. We did not observe any significant reductions in dopamine, noradrenaline or DOPAC concentrations in any brain region of paraquat treated rats as compared with controls. On the contrary, dopamine concentrations in the striatim were significantly elevated in paraquat treated animals following a 15 day paraquat dosing regime. We attribute these changes in catecholamine concentrations to the general toxicity of paraquat which produces a stress response. In conclusion, we could not find any evidence that multiple paraquat dosing can lead to changes in locomotor activity or grip strength. In addition, the absence of neuropathology or changes in neurochemistry in the nigrostriatal tract demonstrates that paraquat does not behave like MPP+(N-methyl-4-phenylpyridinium), the neurotoxic metabolite of MPTP.
Widdowson
P S
PS
Neurotoxicology Research Group, ZENECA Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Farnworth
M J
MJ
Upton
R
R
Simpson
M G
MG
D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects*; D004298:Dopamine / Q000032:analysis; D004334:Drug Administration Schedule; D005106:Exploratory Behavior / Q000187:drug effects; D006540:Herbicides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D009474:Neurons / Q000187:drug effects; D010269:Paraquat / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000032:analysis; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects*; D014018:Tissue Distribution
D006540:Herbicides; D011956:Receptors, Cell Surface; D010269:Paraquat; D004298:Dopamine