Vol. 286, Issue 1, 334-340, July 1998

Effects of the Abused Solvent Toluene on Recombinant N-Methyl-D-Aspartate and non-N-Methyl-D-Aspartate Receptors Expressed in Xenopus Oocytes¹

Silvia L. Cruz, Tooraj Mirshahi, Brian Thomas, Robert L. Balster and John J. Woodward

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia (T.M., R.L.B., J.J.W.); Departamento de Farmacología y Toxicología, CINVESTAV, IPN, Apartado Postal 22026, 14000 Mexico DF, Mexico (S.L.C.) and Center for Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina (B.T.)

Previous studies have shown that toluene, which is commonly abused, depresses neuronal activity and causes behavioral effects in both animals and man similar to those observed for ethanol. In this study, the oocyte expression system was used to test the hypothesis that toluene, like ethanol, inhibits the function of ionotropic glutamate receptors. Oocytes were injected with mRNA for specific N-methyl-D-aspartate (NMDA) or non-NMDA subunits and currents were recorded using conventional two-electrode voltage clamp. To enhance the low water solubility of toluene, drug solutions were prepared by mixing toluene with alkamuls (ethoxylated castor oil) at a 1:1 ratio (v:v) and diluting this mixture to the appropriate concentration with barium-containing normal frog Ringer solution. Alkamuls, up to 0.1%, had no significant effects on membrane leak currents or on NMDA-induced currents. Toluene, up to ~9 mM, had only minor effects on membrane leak currents but dose-dependently inhibited NMDA-mediated currents in oocytes. The inhibition of NMDA receptor currents by toluene was rapid, reversible and the potency for toluene's effects was subunit dependent. The NR1/2B subunit combination was the most sensitive with an IC₅₀ value for toluene-induced inhibition of 0.17 mM. The NR1/2A and NR1/2C receptors were 6- and 12-fold less sensitive with IC₅₀ values of 1.4 and 2.1 mM, respectively. In contrast, toluene up to ~9 mM did not inhibit kainate-induced currents in oocytes expressing GluR1, GluR1+R2 or GluR6 subunits. These results suggest that some of the effects of toluene on neuronal activity and behavior may be mediated by inhibition of NMDA receptors.