EFFECTS OF THE ABUSED SOLVENT TOLUENE ON RECOMBINANT N-METHYL-D-ASPARTATE AND NON-N-METHYL-D-ASPARTATE RECEPTORS EXPRESSED IN XENOPUS OOCYTES

Previous studies have shown that toluene, which is commonly abused, de presses neuronal activity and causes behavioral effects in both animal s and man similar to those observed for ethanol. In this study, the oo cyte expression system was used to test the hypothesis that toluene, l ike ethanol, inhibits the function of ionotropic glutamate receptors. Oocytes were injected with mRNA for specific N-methyl-D-aspartate (NMD A) or non-NMDA subunits and currents were recorded using conventional two-electrode voltage clamp. To enhance the low water solubility of to luene, drug solutions were prepared by mixing toluene with alkamuls (e thoxylated castor oil) at a 1:1 ratio (v:v) and diluting this mixture to the appropriate concentration with barium-containing normal frog Ri nger solution. Alkamuls, up to 0.1%, had no significant effects on mem brane leak currents or on NMDA-induced currents. Toluene, up to simila r to 9 mM, had only minor effects on membrane leak currents but dose-d ependently inhibited NMDA-mediated currents in oocytes. The inhibition of NMDA receptor currents by toluene was rapid, reversible and the po tency for toluene's effects was subunit dependent. The NR1/2B subunit combination was the most sensitive with an IC50 value for toluene-indu ced 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, respective ly. In contrast, toluene up to similar to 9 mM did not inhibit kainate -induced currents in oocytes expressing GluR1, GluR1 + R2 or GluR6 sub units. These results suggest that some of the effects of toluene on ne uronal activity and behavior may be mediated by inhibition of NMDA rec eptors.