Benzodiazepine-like discriminative stimulus effects of toluene vapor

Abstract

In vitro studies show that the abused inhalant toluene affects a number of ligand-gated ion channels.The two most consistently implicated of these are γ-aminobutyric acid type A(GABAA) receptors which are positively modulated by toluene and N-methyl-D-aspartate(NMDA) receptors which are negatively modulated by toluene. Behavioral studies also suggest an interaction of toluene with GABAA and/or NMDA receptors but it is unclear if these receptors underlie the abuse-related intoxicating effects of toluene. Seventeen B6SJLF1/J mice were trained using a two-choice operant drug discrimination procedure to discriminate 10 min of exposure to 2000 ppm toluene vapor from 10 min of exposure to air. The discrimination was acquired in a mean of 65 training sessions. The stimulus effects of 2000 ppm toluene vapor were exposure concentration-dependent but rapidly diminished following the cessation of vapor exposure. The stimulus effects of toluene generalized to the chlorinated hydrocarbon vapor perchloroethylene but not 1,1,2-trichloroethane nor the volatile anesthetic isoflurane. The competitive NMDA antagonist CGS-19755, the uncompetitive antagonist dizocilpine and the glycine-site antagonist L701,324 all failed to substitute for toluene. The classical nonselective benzodiazepines midazolam and chlordiazepoxide produced toluene-like stimulus effects but the alpha 1 subunit preferring positive GABAA modulator zaleplon failed to substitute for toluene. The barbiturates pentobarbital and methohexital and the GABAA positive modulator neurosteroid allopregnanolone did not substitute for toluene. These data suggest that the stimulus effects of toluene may be at least partially mediated by benzodiazepine-like positive allosteric modulation of GABAA receptors containing alpha 2, 3 or 5 subunits.

Fig. 1

Toluene substitution curve for tests sessions conducted after increasing post-exposure delays following 10 min of 2000 ppm toluene vapor exposure. The data points shown are based on the first min of each 5-min test session. Point above Air represents the results of an air exposure control session conducted immediately after removal from the inhalant exposure chamber. Mean (± S.E.M.) percentages toluene-lever responding at post-exposure discrimination session test delays of 3, 5, 10, 20 and 30 min are shown in filled squares.

Fig. 2

Dose-effect curves for midazolam (filled squares), zaleplon (open circles) and chlordiazepoxide (open triangles) in mice trained to discriminate 2000 ppm inhaled toluene vapor from air (n=8, 7 and 8, respectively). The data presented are based on the first min of each 5-min test session. Points above Air (open symbols) and Tol (filled symbols) represent the results of air and 2000 ppm inhaled toluene exposure control sessions. Mean (± S.E.M.) percentages toluene-lever responding are shown in the upper panel and mean (± S.E.M.) response rates in responses/sec are shown in the bottom panel. Numbers in parentheses indicate the number of animals out of the group that emitted sufficient responses to be included in the percentage toluene-lever selection curve. * indicates statistically significant (P < 0.05) difference from air control response rate.