Evaluating the NMDA-glutamate receptor as a site of action for toluene, in vivo.
Acute exposure to toluene and other volatile organic solvents 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 MK801 (antagonist). Dose levels of 2.5 mg/kg NMDA and 0.1 mg/kg MK801 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 MK801. 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, ip), or MK801 (0.1 mg/kg, ip) and 10 min 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 MK801 prior to toluene exposure blocked the F2 amplitude decreases caused by toluene (n = 9). However, when 0.1 mg/kg MK801 was administered 20 min 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.
Bale
Ambuja S
AS
Neurotoxicology Division, MD B105-05, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Jackson
Meredith D
MD
Krantz
Quentin Todd
QT
Benignus
Vernon A
VA
Bushnell
Philip J
PJ
Shafer
Timothy J
TJ
Boyes
William K
WK
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005074:Evoked Potentials, Visual / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D012997:Solvents; D014050:Toluene / Q000037:antagonists & inhibitors / Q000633:toxicity*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012997:Solvents; D014050:Toluene; D016291:Dizocilpine Maleate