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

Abstract

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.

Malathion Neurotoxic Effects on Dopaminergic System in Mice: Role of Inflammation

“…These findings denote proinflammatory mechanism of malathion induced neurodegeneration which support previous reports on OPs mechanisms of neurotoxicity and aetiological pathways for dopaminergic system damage [36,37].…”

Muscarinic receptors acting at pre- and post-synaptic sites differentially regulate dopamine/DARPP-32 signaling in striatonigral and striatopallidal neurons

“…Studies in M5 null and mutant mice Thomsen et al, 2005;Wang et al, 2004) support the idea that dysfunction of dopamine/DARPP-32 signaling activated by muscarinic receptors, especially by M5 receptors, may contributes to the pathophysiology of schizophrenia and drug addiction. In addition, dopamine/DARPP-32 signaling can be a molecular target that mediates neurotoxicity of organophosphate (Torres-Altoro et al, 2011).…”

Chronic exposure to chlorpyrifos triggered body weight increase and memory impairment depending on human apoE polymorphisms in a targeted replacement mouse model

“…CPF exerts its insecticidal activity by irreversibly inhibiting cholinesterases (ChE) and disrupting cholinergic function in the nervous system. While the acute neurotoxicity of CPF has been associated with systemic and brain ChE inhibition, an increasing body of experimental data suggests that CPF also targets non-cholinergic neurotransmitters such as serotonin, dopamine, glutamate and hormones [54,70,74]. Considering the number of potential targets, CPF exposure would be expected to have a wide range of effects.…”