Effects of inhaled toluene and 1,1,1-trichloroethane on seizures and death produced by N-methyl-D-aspartic acid in mice

Evidence exists that some abused solvents have N-methyl-D-aspartic acid (NMDA) antagonist activity, although which of their effects may be related to this mechanism is not well understood. The effects of toluene and 1,1,1-trichloroethane (TCE) on NMDA-induced seizures in mice were studied using three experimental protocols: (a) animals injected i.p. with 120 or 170 mg/kg NMDA and immediately afterwards exposed to solvent vapors or air for 30 min (co-exposure protocol); (b) mice exposed for 30 min to solvent or air, then injected with NMDA and placed in the chamber for a second 30-min exposure (pre-exposure + co-exposure protocol); and (c) mice that inhaled 4000 ppm toluene or air for 30 min twice a day, 6 h apart, for 7 days, and were injected with 120 mg/kg NMDA immediately before a 30-min toluene exposure (repeated exposure protocol). When given acutely, toluene, but not TCE, produced concentration-dependent protection against NMDA-induced seizures. Higher concentrations of toluene were also effective against the lethal effects produced by 170 mg/kg NMDA. Clearer effects were seen when the pre-exposure + co-exposure protocol was followed. Under these conditions the IC50 for toluene was 739 ppm (653-825) against seizure occurrence and 2127 ppm (1966-2288) against lethality. Repeated exposure to toluene did not result in tolerance to its anticonvulsant effects. These results are consistent with the in vitro effects described for toluene as a noncompetitive NMDA antagonist and as a compound that enhances GABAergic transmission. The lack of protective effects of TCE is not consistent with its in vitro actions. (C) 2002 Elsevier Science B.V. All rights reserved.