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

The 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.

Thirty mice were trained to discriminate 10 min of 12,000 ppm TCE vapor exposure from air using an operant procedure. Substitution tests were then conduced with positive GABA(A) receptor modulators and/or NMDA receptor antagonists.

The nonselective benzodiazepines midazolam and diazepam produced 62% and 61% and the barbiturate pentobarbital produced 68% TCE-lever selection. Zaleplon, an alpha1 subunit-preferring positive GABA(A) receptor benzodiazepine-site positive modulator resulted in 29% TCE-lever selection. The direct extrasynaptic GABA(A) 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.

The results suggest that the discriminative stimulus effects of TCE are fairly selectively mediated by positive modulation of GABA(A) receptors. The failure of gaboxadol to substitute and the poor substitution by zaleplon suggests that extrasynaptic GABA(A) receptors as well as GABA(A) receptors containing alpha1 subunits and are not involved in transducing the discriminative stimulus of TCE. Studies with additional GABA(A) benzodiazepine-site positive modulators will be necessary to confirm and extend these findings.