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 IC(50) 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.
Cruz
Silvia Lorenia
SL
Departamento de Farmacobiología, Cinvestav, IPN. Calzada de los Tenorios #235, Col. Granjas Coapa, 14330 Mexico, D.F., Mexico. cruz_farma@yahoo.com
Gauthereau
Marcia Yvette
MY
Camacho-Muñoz
Cynthia
C
López-Rubalcava
Carolina
C
Balster
Robert L
RL
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D013287:Illicit Drugs / Q000633:toxicity; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000633:toxicity; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D012997:Solvents / Q000627:therapeutic use; D013997:Time Factors; D014050:Toluene / Q000627:therapeutic use*; D014240:Trichloroethanes / Q000627:therapeutic use*
D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D013287:Illicit Drugs; D012997:Solvents; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; D014050:Toluene; D016202:N-Methylaspartate