Neonatal toluene exposure alters agonist and antagonist sensitivity and NR2B subunit expression of NMDA receptors in cultured cerebellar granule neurons.
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. Sprague-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.
Chen
Hwei-Hsien
HH
Graduate Institute of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan.
Wei
Chao-Ting
CT
Lin
Yi-Ruu
YR
Chien
Te-Hsiung
TH
Chan
Ming-Huan
MH
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014050:Toluene / Q000633:toxicity*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014050:Toluene