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Vol. 57, Issue 6, 1199-1205, June 2000
-Aminobutyric AcidA Receptor Function
Is Enhanced by Inhaled Drugs of Abuse
Department of Physiology and Pharmacology, Wake Forest University
School of Medicine, Winston-Salem, North Carolina (M.J.B., J.L.W.,
S.J.M.); and Department of Anesthesia, University of California, San
Francisco, California (E.I.E., D.H.G.)
Inhalable solvents possess significant abuse liability and produce many
of the neurobehavioral effects typically associated with central
nervous system-depressant agents, including motor incoordination,
anxiolysis, and the elicitation of signs of physical dependence on
withdrawal. We tested the hypothesis that the commonly abused solvents
toluene, 1,1,1-trichloroethane (TCE), and trichloroethylene (TCY)
affect ligand-gated ion channel activity, as do other classes of
central nervous system-depressive agents. TCE and toluene, like
ethanol, reversibly enhanced 
-aminobutyric acid (GABA)A receptor-mediated synaptic currents in rat hippocampal slices. All
three inhalants significantly and reversibly enhanced
neurotransmitter-activated currents at 
1
1 GABAA and
1 glycine receptors expressed in Xenopus oocytes. We
previously identified specific amino acids of glycine and
GABAA receptor subunits mediating alcohol and volatile
anesthetic enhancement 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 seen in all these mutants. However, the potentiating effects of TCE were abolished 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 abuse affect ligand-gated ion channels, and that the molecular sites of action of
these compounds may overlap with those of ethanol and the volatile anesthetics.
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