Discriminative stimulus effects of inhaled 1,1,1-trichloroethane in mice: comparison to other hydrocarbon vapors and volatile anesthetics

Abstract

Rationale-Because the toxicity of many inhalants precludes evaluation in humans, drug discrimination, an animal model of subjective effects, can be used to gain insights on their poorly understood abuse-related effects.Objectives-The purpose of the present study was to train a prototypic inhalant that has known abuse liability, 1,1,1-trichloroethane (TCE), as a discriminative stimulus in mice and compare it to other classes of inhalants.Methods-Eight B6SJLF1/J mice were trained to discriminate 10 min of exposure to 12000 ppm inhaled TCE vapor from air and seven mice were trained to discriminate 4000 ppm TCE from air. Tests were then conducted to characterize the discriminative stimulus of TCE and to compare it to representative aromatic and chlorinated hydrocarbon vapors, volatile halogenated anesthetics as well as an odorant compound.Results-Only the 12000 ppm TCE versus air discrimination group exhibited sufficient discrimination accuracy for substitution testing. TCE vapor concentration-and exposure timedependently substituted for the 12000 ppm TCE vapor training stimulus. Full substitution was produced by trichloroethylene, toluene, enflurane and sevoflurane. Varying degrees of partial substitution were produced by the other volatile test compounds. The odorant, 2-butanol, did not produce any substitution for TCE.Conclusions-The discriminative stimulus effects of TCE are shared fully or partially by chlorinated and aromatic hydrocarbons as well as by halogenated volatile anesthetics. However, these compounds can be differentiated from TCE both quantitatively and qualitatively. It appears that the degree of similarity is not solely a function of chemical classification but may also be dependent upon the neurochemical effects of the individual compounds.

Pharmacological Characterization of the Discriminative Stimulus of Inhaled 1,1,1-Trichloroethane

“…This result suggests common mechanisms may underlie the discriminative stimulus effects of both compounds. The present halothane data are consistent with results from a previous experiment showing that the halogenated ether vapor anesthetics enflurane and sevoflurane also fully substitute for TCE (Shelton, 2009). Interestingly, a third halogenated ether isoflurane failed to completely substitute for TCE in the prior study, suggesting that there may be some subtle differences in the in vivo pharmacological effects of volatile anesthetics that can be detected by drug discrimination.…”

“…We have previously examined the substitution profiles of representative inhalants in animals trained to discriminate TCE from air (Shelton, 2009). My laboratory and others have also assessed cross-substitution of TCE in animals trained to discriminate other drugs from vehicle Shelton and Balster, 2004).…”

“…These mice were supplemented with an additional 12 adult male B6SJLF1/J mice used only for TCE blood concentration analysis. The B6SJLF1/J strain has been used extensively in my laboratory for drug discrimination studies with TCE and toluene vapor providing knowledge of appropriate test conditions (Shelton, 2007(Shelton, , 2009Shelton and Slavova-Hernandez, 2009). The mice were individually housed on a 12-h light/dark cycle (lights on 7:00 AM).…”

“…Drug discrimination is an animal model of the abuse-related intoxicating effects of drugs in humans and has been used extensively to examine other classes of abused drugs. However, few studies have examined the discriminative stimulus effects of inhalants, in any fashion, and only one has used TCE as a training drug (Shelton, 2009). In that experiment, the volatile anesthetic vapors enflurane and sevoflurane produced full substitution in mice trained to discriminate TCE vapor from air.…”

Volatile Solvents as Drugs of Abuse: Focus on the Cortico-Mesolimbic Circuitry

“…Mice will fully discriminate vaporized toluene from air at concentrations between 4000 and 12000 p.p.m., and the discriminative time course mirrors the falling blood concentration after vapor concentration (Shelton and Slavova-Hernandez, 2009). Similarly, TCE can act as a discriminative stimulus, and other volatile solvents like toluene, ethylbenzene, o-xylene, TCY, and PERC all substitute for TCE (Shelton, 2009). In terms of selective channel agonists or antagonists, the benzodiazepine (BZ) midazolam partially substitutes for TCE, an effect that is blocked by the BZ-site antagonist flumazenil.…”