TY - JOUR
T1 - Organophosphates dysregulate dopamine signaling, glutamatergic neurotransmission, and induce neuronal injury markers in striatum
AU - Torres-Altoro, Melissa I.
AU - Mathur, Brian N.
AU - Drerup, Justin M.
AU - Thomas, Rachel
AU - Lovinger, David M.
AU - O'Callaghan, James P.
AU - Bibb, James A.
PY - 2011/10
Y1 - 2011/10
N2 - 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 Mr 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.
AB - 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 Mr 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.
KW - Gulf War illness
KW - chlorpyrifos
KW - dopamine
KW - insecticide
KW - neurotoxicity
KW - organophosphate
UR - http://www.scopus.com/inward/record.url?scp=80053572218&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053572218&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2011.07428.x
DO - 10.1111/j.1471-4159.2011.07428.x
M3 - Article
C2 - 21848865
AN - SCOPUS:80053572218
SN - 0022-3042
VL - 119
SP - 303
EP - 313
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 2
ER -