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ToxSci Advance Access originally published online on February 2, 2005
Toxicological Sciences 2005 85(1):666-674; doi:10.1093/toxsci/kfi100
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Toxicological Sciences vol. 85 no. 1 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Neonatal Toluene Exposure Alters Agonist and Antagonist Sensitivity and NR2B Subunit Expression of NMDA Receptors in Cultured Cerebellar Granule Neurons

Hwei-Hsien Chen*, Chao-Ting Wei{ddagger}, Yi-Ruu Lin{ddagger}, Te-Hsiung Chien* and Ming-Huan Chan{dagger},1

* Graduate Institute of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan; {dagger} Department of Pharmacology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan; and {ddagger} Graduate Institute of Medical Sciences, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan

Received November 23, 2004; accepted January 29, 2005

Toluene has been reported to antagonize the function of N-methyl-D-aspartate (NMDA) receptors. In this study, the effects of neonatal toluene exposure on NMDA receptors in primarily cultured cerebellar granule neurons were examined. Spargue-Dawley rats were treated with toluene (0, 200, 500, and 1000 mg/kg, i.p.) from postnatal day (PN) 4 to PN 7. Under toluene-free conditions, Ca2+ signals of cultured neurons in response to glutamate and NMDA were measured for up to 14 days. The expression of NMDA receptor subunits (NR1, NR2A, and NR2B) at 5–14 days in vitro (DIV) were also determined. Neonatal toluene exposure dose-dependently reduced intracellular Ca2+ signals in response to glutamate/glycine and NMDA/glycine in cultured cerebellar granule neurons, and these effects were gradually decreased with time. Such toluene exposure did not influence the inhibition of Mg2+ or MK801 on NMDA-evoked responses, but it decreased the potency of ifenprodil (an NR2B preferring antagonist). The protein levels of NMDA receptor subunit NR2B were consistently reduced by toluene exposure at 5 DIV, but not at 14 DIV. These results demonstrate that neonatal toluene exposure induces long-term but reversible changes in the function and composition of NMDA receptors. Such changes during developmental stages may contribute to the cerebellar dysfunction observed in fetal solvent syndrome.

Key Words: toluene; neonatal; NMDA receptor; Ca2+; NR2B; cerebellar granule neurons.


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