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Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum.

Torres-Altoro MI; Mathur BN; Drerup JM; Thomas R; Lovinger D; O'Callaghan JP; Bibb JA

J Neurochem 2011 Oct; 119(2):303-313

https://doi.org/10.1111/j.1471-4159.2011.07428.x

20039410

The neurological effects of organophosphate pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here we characterized the effects of the broadly-used insecticide chlorpyrifos on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. Chlorpyrifos potentiated PKA-dependent phosphorylation of the striatal protein DARPP-32 and the GluR1 subunit of AMPA receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide DEET. This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration.

Organo-phosphorus-compounds; Organo-phosphorus-pesticides; Neurological-reactions; Neurological-system; Neurotransmitters; Pesticides; Hazardous-materials; Insecticides; Neuromotor-function; Neuromotor-system; Phosphates; Proteins; Glutamates; Biological-warfare-agents; Military-personnel; Neurotoxic-effects; Neurotoxins; Toxic-effects; Toxic-materials; Humans; Animal-studies; Animals; Author Keywords: insecticide; dopamine; neurotoxicity; organophosphate; chlorpyrifos; Gulf War Illness

James A. Bibb, Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, NC5.410 Dallas, TX 75390-9070

JONRA9

2921-88-2; 134-62-3; 55-91-4; 51-61-6

20111001

Journal Article

james.bibb@utsouthwestern.edu

2012

2

0022-3042

HELD

Manufacturing

Journal of Neurochemistry

TX; MD; WV