Glycine and gamma-aminobutyric Acid(A) receptor function is enhanced by inhaled drugs of abuse

Inhalable solvents possess significant abuse liability and produce many of the neurobehavioral effects typically associated with central nervous syste m-depressant agents, including motor incoordination, anxiolysis, and the el icitation of signs of physical dependence on withdrawal. We tested the hypo thesis that the commonly abused solvents toluene, 1,1,1-trichloroethane (TC E), and trichloroethylene (TCY) affect ligand-gated ion channel activity, a s do other classes of central nervous system-depressive agents. TCE and tol uene, like ethanol, reversibly enhanced gamma-aminobutyric acid (GABA)(A) r eceptor-mediated synaptic currents in rat hippocampal slices. All three inh alants significantly and reversibly enhanced neurotransmitter-activated cur rents at alpha 1 beta 1 GABA(A) and alpha 1 glycine receptors expressed in Xenopus oocytes. We previously identified specific amino acids of glycine a nd GABA(A) receptor subunits mediating alcohol and volatile anesthetic enha ncement of receptor function. Toluene, TCE, and TCY were tested on several glycine receptor mutants, some of which were insensitive to ethanol and/or enflurane. Toluene and TCY enhancement of glycine receptor function was see n in all these mutants. However, the potentiating effects of TCE were aboli shed in three mutants and enhanced in two, a pattern more akin to that seen with enflurane than ethanol. These data suggest that inhaled drugs of abus e affect ligand-gated ion channels, and that the molecular sites of action of these compounds may overlap with those of ethanol and the volatile anest hetics.