Organophosphorus insecticides (OPs) elicit toxicity by inhibiting acetylcholinesterase, leading to acetylcholine accumulation at cholinergic synapses, excessive stimulation of cholinergic receptors and signs of acute toxicity (e.g., tremors, excessive secretions, seizures). The OPs parathion and chlorpyrifos elicit similar degrees of acetylcholinesterase inhibition and brain acetylcholine accumulation in vivo, yet markedly different degrees of toxicity. Accumulation of acetylcholine leads to """"""""recruitment"""""""" of non-cholinergic signaling important in the expression of OP toxicity. Endocannabinoids (eCBs, e.g., anandamide, 2-arachidonyl glycerol, 2-AG) modulate neurotransmission by activating presynaptic cannabinoid receptors and inhibiting neurotransmitter release. Synthesis and release of eCBs can be increased by anticholinesterases through postsynaptic neuron depolarization or in a receptor- mediated fashion by activation muscarinic M1/M3 receptors. Furthermore, some OPs may directly alter eCB signaling by binding to cannabinoid receptors and/or inhibiting eCB metabolizing enzymes. We hypothesize that eCBs modulate the expression of anticholinesterase toxicity via inhibition of the release of downstream neurotransmitters involved in expression of anticholinesterase toxicity, and that differential direct actions of chlorpyrifos and parathion on the eCB signaling pathway lead to selective toxicity. Studies in aim 1 will evaluate the hypothesis that eCB signaling modulates cholinergic toxicity using pharmacological approaches. Preliminary studies indicate that chlorpyrifos selectively increases extracellular 2-AG levels in hippocampus. Studies in aim 2 will compare time-dependent effects of parathion and chlorpyrifos on both tissue and basal and depolarization-evoked extracellular eCB levels, and evaluate possible cellular mechanisms for OP-selective changes. Increases in dopaminergic, GABAergic and glutamatergic signaling have all been implicated in anticholinesterase toxicity.
Aim 3 will compare in vitro, ex vivo and in vivo changes in these non-cholinergic signaling pathways elicited by parathion and chlorpyrifos. Finally, studies in aim 4 will compare sensitivity of CB1+/+ and CB1-/- mice to acute and subacute toxicity from parathion and chlorpyrifos and evaluate possible changes in neurotransmitter release elicited by parathion and/or chlorpyrifos and mediated through the CB1 receptor.

Public Health Relevance

Project Narrative Many neurotoxicants including organophosphorus anticholinesterases elicit toxicity by disrupting the dynamic balance between synthesis, release and inactivation of neurotransmitters. Endocannabinoid signaling is a widespread neuromodulatory process that regulates neurotransmission via inhibition of neurotransmitter release. This project will evaluate the role of endocannabinoid signaling in the expression of anticholinesterase toxicity and determine whether its differential modulation participates in selective toxicity.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Kirshner, Annette G
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Oklahoma State University Stillwater
Schools of Veterinary Medicine
United States
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Pope, Carey N; Brimijoin, Stephen (2018) Cholinesterases and the fine line between poison and remedy. Biochem Pharmacol 153:205-216
Liu, Jing; Parsons, Loren; Pope, Carey (2015) Comparative effects of parathion and chlorpyrifos on endocannabinoid and endocannabinoid-like lipid metabolites in rat striatum. Neurotoxicology 50:20-7
Liu, Jing; Pope, Carey (2015) The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats. Neurotoxicology 46:12-8
Liu, Jing; Parsons, Loren; Pope, Carey (2013) Comparative effects of parathion and chlorpyrifos on extracellular endocannabinoid levels in rat hippocampus: influence on cholinergic toxicity. Toxicol Appl Pharmacol 272:608-15
Baireddy, Praveena; Liu, Jing; Hinsdale, Myron et al. (2011) Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice. Toxicol Appl Pharmacol 256:324-9
Pope, C; Mechoulam, R; Parsons, L (2010) Endocannabinoid signaling in neurotoxicity and neuroprotection. Neurotoxicology 31:562-71
Ray, Anamika; Liu, Jing; Ayoubi, Patricia et al. (2010) Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats. Toxicol Appl Pharmacol 248:144-55
Wright, Linnzi K M; Liu, Jing; Nallapaneni, Anuradha et al. (2010) Behavioral sequelae following acute diisopropylfluorophosphate intoxication in rats: comparative effects of atropine and cannabinomimetics. Neurotoxicol Teratol 32:329-35
Ray, A; Liu, J; Karanth, S et al. (2009) Cholinesterase inhibition and acetylcholine accumulation following intracerebral administration of paraoxon in rats. Toxicol Appl Pharmacol 236:341-7
Nallapaneni, Anuradha; Liu, Jing; Karanth, Subramanya et al. (2008) Pharmacological enhancement of endocannabinoid signaling reduces the cholinergic toxicity of diisopropylfluorophosphate. Neurotoxicology 29:1037-43

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