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-17955, 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.

Pharmacological Classification of the Abuse-Related Discriminative Stimulus Effects of Trichloroethylene Vapor

“…In contrast, isoflurane is a poor analgesic [59] suggesting some differences in mechanism which we may also be detecting in our discrimination assay. The present findings are generally in agreement with previous experiments from our laboratory in which the vapor anesthetic halothane produced full substitution in mice trained to discriminate 1,1,1-trichloroethane vapor from air [37] and both 1,1,1-trichloroethane and tetrachloroethylene produced complete substitution in mice trained to discriminate toluene vapor from air [38]. In aggregate, these data demonstrate there is substantial overlap in the discriminative stimulus effects of a number of different classes of volatile inhalants including aromatic and chlorinated hydrocarbons as well as vapor anesthetics.…”

“…We have previously demonstrated that the discriminative stimulus effects of 1,1,1-trichloroethane are mediated at least partially by classical benzodiazepine and barbiturate-like positive GABA A receptor modulation but appear to not be dependent upon NMDA antagonist activity, nicotinic acetylcholine receptor modulation or mu opioid agonist effects [36; 37]. Likewise our data show that GABA A modulators substitute in mice trained to discriminate toluene although interestingly, unlike 1,1,1-trichlorothane, the stimulus effects of toluene are mimicked more completely by classical benzodiazepines than barbiturates [38]. These results suggest that while there are substantial commonalities between the stimulus effects of aromatic and chlorinated hydrocarbons, potentially important pharmacological differences do exist.…”

“…This latter interpretation is strengthened by data from a prior study in our laboratory in which MK-801, CGS-19755 and L701,324 all produced exclusively vehicle-appropriate responding in mice trained to discriminate 1,1,1-trichloroethane vapor from air [36]. In general, the present results suggest that attenuation of NMDA receptor function plays little if any role in the discriminative stimulus effects of chlorinated hydrocarbons.This overarching finding extends to toluene as well where we have demonstrated that competitive, uncompetitive and glycine-site NMDA antagonists do not elicit toluene-like discriminative stimulus effects [38], again despite very strong evidence that toluene inhibits NMDA receptor function in other assays [6; 13; 17; 18; 60; 63; 64]. Interestingly, although NMDA receptor antagonism does not appear to underlie the discriminative stimulus effects of chlorinated or aromatic hydrocarbons it, in addition to GABA A receptor positive modulation, does appear to be involved in transducing the stimulus effects of the volatile anesthetic isoflurane [46].…”

“…Even following the short training exposure duration of 10 min, it required between 30 and 60 min before trichloroethylene-lever responding returned to near that of the air control (Figure 1, bottom panel). This is compared to 10-20 min to reach a similar level of recovery in mice trained to discriminate toluene [38] and less than 10 min for 1,1,1-trichloroethane (unpublished observation). Likewise the onset of stimulus effects resulting from trichloroethylene exposure was also slower than that of 1,1,1-trichloroethane [37].…”

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

“…In contrast, Ro15-4513 completely blocked d-methamphetamine, toluene and diazepam- facilitated ICSS. While toluene has positive GABA A modulatory effects (Beckstead et al 2000; Williams et al 2005; Shelton and Nicholson 2013; Beckley and Woodward 2013), d-methamphetamine does not (Hondebrink et al 2011), supporting our hypothesis that negative allosteric GABA A modulation via the BDZ site can strongly affect the reward-related effects of drugs of abuse, regardless of their specific pharmacological mechanism of action.…”