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Title: Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice

Abstract

Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n = 5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 {mu}M) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypesmore » ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: Black-Right-Pointing-Pointer C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. Black-Right-Pointing-Pointer Wild type and cannabinoid CB1 receptor knockout littermates responded similarly to the toxic effects of chlorpyrifos. Black-Right-Pointing-Pointer OP-induced changes in acetylcholine release appeared sensitive to modulation by CB1-mediated endocannabinoid signaling.« less

Authors:
; ; ;
Publication Date:
OSTI Identifier:
22212534
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 256; Journal Issue: 3; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETYLCHOLINE; ANIMAL TISSUES; CEREBELLUM; CHOLINESTERASE; GENOTYPE; HIPPOCAMPUS; IN VITRO; INSECTICIDES; KNOCK-OUT REACTIONS; MICE; PEANUT OIL; RATS; RECEPTORS; TOXICITY

Citation Formats

Baireddy, Praveena, Liu, Jing, Hinsdale, Myron, and Pope, Carey, E-mail: carey.pope@okstate.edu. Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice. United States: N. p., 2011. Web. doi:10.1016/J.TAAP.2011.05.018.
Baireddy, Praveena, Liu, Jing, Hinsdale, Myron, & Pope, Carey, E-mail: carey.pope@okstate.edu. Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice. United States. doi:10.1016/J.TAAP.2011.05.018.
Baireddy, Praveena, Liu, Jing, Hinsdale, Myron, and Pope, Carey, E-mail: carey.pope@okstate.edu. Tue . "Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice". United States. doi:10.1016/J.TAAP.2011.05.018.
@article{osti_22212534,
title = {Comparative effects of chlorpyrifos in wild type and cannabinoid Cb1 receptor knockout mice},
author = {Baireddy, Praveena and Liu, Jing and Hinsdale, Myron and Pope, Carey, E-mail: carey.pope@okstate.edu},
abstractNote = {Endocannabinoids (eCBs) modulate neurotransmission by inhibiting the release of a variety of neurotransmitters. The cannabinoid receptor agonist WIN 55.212-2 (WIN) can modulate organophosphorus (OP) anticholinesterase toxicity in rats, presumably by inhibiting acetylcholine (ACh) release. Some OP anticholinesterases also inhibit eCB-degrading enzymes. We studied the effects of the OP insecticide chlorpyrifos (CPF) on cholinergic signs of toxicity, cholinesterase activity and ACh release in tissues from wild type (+/+) and cannabinoid CB1 receptor knockout (-/-) mice. Mice of both genotypes (n = 5-6/treatment group) were challenged with CPF (300 mg/kg, 2 ml/kg in peanut oil, sc) and evaluated for functional and neurochemical changes. Both genotypes exhibited similar cholinergic signs and cholinesterase inhibition (82-95% at 48 h after dosing) in cortex, cerebellum and heart. WIN reduced depolarization-induced ACh release in vitro in hippocampal slices from wild type mice, but had no effect in hippocampal slices from knockouts or in striatal slices from either genotype. Chlorpyrifos oxon (CPO, 100 {mu}M) reduced release in hippocampal slices from both genotypes in vitro, but with a greater reduction in tissues from wild types (21% vs 12%). CPO had no significant in vitro effect on ACh release in striatum. CPF reduced ACh release in hippocampus from both genotypes ex vivo, but reduction was again significantly greater in tissues from wild types (52% vs 36%). In striatum, CPF led to a similar reduction (20-23%) in tissues from both genotypes. Thus, while CB1 deletion in mice had little influence on the expression of acute toxicity following CPF, CPF- or CPO-induced changes in ACh release appeared sensitive to modulation by CB1-mediated eCB signaling in a brain-regional manner. -- Highlights: Black-Right-Pointing-Pointer C57Bl/6 mice showed dose-related cholinergic toxicity following subcutaneous chlorpyrifos exposure. Black-Right-Pointing-Pointer Wild type and cannabinoid CB1 receptor knockout littermates responded similarly to the toxic effects of chlorpyrifos. Black-Right-Pointing-Pointer OP-induced changes in acetylcholine release appeared sensitive to modulation by CB1-mediated endocannabinoid signaling.},
doi = {10.1016/J.TAAP.2011.05.018},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 256,
place = {United States},
year = {Tue Nov 15 00:00:00 EST 2011},
month = {Tue Nov 15 00:00:00 EST 2011}
}