Benzodiazepine-like discriminative stimulus effects of toluene vapor

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.