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

Document Type

Article

Abstract

The neurological effects of organophosphate (OP) 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 (CPF) on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. CPF potentiated protein kinase A (PKA)-dependent phosphorylation of the striatal protein dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) and the glutamate receptor 1 (GluR1) subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (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 N,N-diethyl-meta-toluamide (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.

Medical Subject Headings

Animals; Animals, Newborn; Biomarkers; Blotting, Western; Chlorpyrifos; Cholinesterase Inhibitors; Corpus Striatum; Cyclin-Dependent Kinase 5; Dopamine; Female; Glutamic Acid; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Neurons; Neurotoxicity Syndromes; Organophosphates; Patch-Clamp Techniques; Phosphorylation; Pyridostigmine Bromide; Receptors, Dopamine D1; Signal Transduction; Synaptic Transmission; tau Proteins

Publication Date

10-1-2011

Publication Title

Journal of neurochemistry

ISSN

1471-4159

Volume

119

Issue

2

First Page

303

Last Page

313

PubMed ID

21848865

Digital Object Identifier (DOI)

10.1111/j.1471-4159.2011.07428.x

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