GABAA-positive modulator selective discriminative stimulus effects of 1,1,1-trichloroethane vapor

Abstract

BackgroundThe abuse-related behavioral effects of inhalant vapors are poorly understood but probably involve multiple neurotransmitter receptor mechanisms. The present study examined the receptor systems responsible for transducing the discriminative stimulus of the abused chlorinated hydrocarbon 1,1,1-trichloroethane (TCE) in mice. MethodsThirty mice were trained to discriminate 10min of 12000ppm TCE vapor exposure from air using an operant procedure. Substitution tests were then conduced with positive GABAA receptor modulators and/or NMDA receptor antagonists. ResultsThe nonselective benzodiazepines midazolam and diazepam produced 62% and 61% and the barbiturate pentobarbital produced 68% TCE-lever selection. Zaleplon, an alpha1 subunit-preferring positive GABAA receptor benzodiazepine-site positive modulator resulted in 29% TCE-lever selection. The direct extrasynaptic GABAA agonist gaboxodol (THIP) and the GABA reuptake inhibitor tiagabine failed to substitute for TCE. No substitution was elicited by a competitive (CGS-19755), noncompetitive (dizocilpine) or glycine-site (L701,324) NMDA antagonist. The mixed benzodiazepine/noncompetitive NMDA antagonist anesthetic Telazol and the anticonvulsant valproic acid exhibited low levels of partial substitution for TCE (38% and 39%, respectively). Ethanol and nitrous oxide failed to substitute for TCE. ConclusionsThe results suggest that the discriminative stimulus effects of TCE are fairly selectively mediated by positive modulation of GABAA receptors. The failure of gaboxadol to substitute and the poor substitution by zaleplon suggests that extrasynaptic GABAA receptors as well as GABAA receptors containing alpha1 subunits and are not involved in transducing the discriminative stimulus of TCE. Studies with additional GABAA benzodiazepine-site positive modulators will be necessary to confirm and extend these findings.