ToxSci Advance Access published online on April 9, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm080
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Published by Oxford University Press 2007.
Evaluating the NMDA-Glutamate Receptor as a Site of Action for Toluene, In Vivo*
1 Neurotoxicology, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 2 Campbell University, Buies Creek, NC 3 Experimental Toxicology, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 4 Human Studies Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC * Current address: Product Safety and Dermal Clinical Research, Colgate-Palmolive Company, Piscataway, NJ 08854
Corresponding author: William K. Boyes, Ph.D., Neurotoxicology Division, MD B105-05, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, Phone: 919-541-7538, Fax: 919-541-4849, Email: boyes.william{at}epa.gov
Received January 31, 2007; revision received March 30, 2007; accepted March 31, 2007
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Abstract |
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Acute exposure to toluene and other volatile organic solvents (VOCs) results in neurotoxicity characterized by nervous system depression, cognitive and motor impairment, and alterations in visual function. In vitro, toluene disrupts the function of N-methyl-D-aspartate (NMDA)-glutamate receptors, indicating that effects on NMDA receptor function may contribute to toluene neurotoxicity. NMDA-glutamate receptors are widely present in the visual system and contribute to pattern-elicited visual evoked potentials (VEPs) in rodents, a measure that is altered by toluene exposure. The present study tested the hypothesis that effects on NMDA receptors contribute to toluene-induced alterations in pattern-elicited VEPs. Prior to examining the effects of NMDA receptor agonists and antagonists on toluene exposed animals, a dose-range study was conducted to determine the optimal dose for NMDA (agonist) and MK-801 (antagonist). Dose levels of 2.5 mg/kg NMDA and 0.1 mg/kg MK-801 were selected from these initial studies. In the second study, Long-Evans rats were exposed to toluene by inhalation and VEPs were measured during toluene exposure in the presence or absence of NMDA or MK-801. Pattern-elicited VEPs were collected by exposing rats to a sinusoidal pattern modulated at a temporal frequency of 4.55 Hz. Following collection of baseline VEPs, rats were injected with either saline, NMDA (2.5 mg/kg i.p.), or MK-801 (0.1 mg/kg, i.p.) and 10 minutes later were exposed to air or toluene (2000 ppm). VEP amplitudes were calculated for 1X (F1) and 2X stimulus frequency (F2). The F2 amplitude was reduced by approximately 60, 60 and 50% in the toluene-exposed groups (TOL): SALINE/TOL (n=11), NMDA/TOL (2.5 mg/kg; n=13), and NMDA/TOL (10 mg/kg, n=11), respectively. Thus, NMDA (2.5 and 10 mg/kg) did not significantly affect toluene-mediated F2 amplitude effects. Administration of 0.1 mg/kg MK-801 prior to toluene exposure blocked the F2 amplitude decreases caused by toluene (n=9). However, when 0.1 mg/kg MK-801 was administered 20 minutes after the onset of toluene exposure, toluene-mediated F2 amplitude decreases persisted despite the challenge by MK801. These data support the hypothesis that acute actions of toluene on pattern-elicited VEPs involve NMDA receptors.
Key Words: NMDA receptor; toluene; visual evoked potentials.
* The information in this document has been funded wholly by the U.S. Environmental Protection Agency. Preliminary data was presented previously at the 22nd International Neurotoxicology Meeting in Research Triangle Park, NC and at the 45th Society of Toxicology Meeting in San Diego, CA. This document has been reviewed by the National Health and Environmental Effects Research Laboratory, and is approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
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