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