title: Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum.
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.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Melissa I
authors.initials: MI
authors.lastname: Torres-Altoro
authors.forename: Brian N
authors.initials: BN
authors.lastname: Mathur
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drerup
authors.forename: Rachel
authors.initials: R
authors.lastname: Thomas
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers; D015153:Blotting, Western; D004390:Chlorpyrifos / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D020258:Neurotoxicity Syndromes / Q000473:pathology* / Q000503:physiopathology; D010755:Organophosphates / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011729:Pyridostigmine Bromide / Q000633:toxicity; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D017447:Receptors, Dopamine D1; D016875:tau Proteins; D018698:Glutamic Acid; D051360:Cyclin-Dependent Kinase 5; D004390:Chlorpyrifos; D011729:Pyridostigmine Bromide; D004298:Dopamine