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

Michael J. Beckstead, Jeff L. Weiner, Edmond I. Eger, Diane H. Gong, S. John Mihic

Research output: Contribution to journalArticlepeer-review

172 Scopus citations

Abstract

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 γ-aminobutyric acid-(GABA)(A) receptor-mediated synaptic currents in rat hippocampal slices. All three inhalants significantly and reversibly enhanced neurotransmitter-activated currents at α1β1 GABA(A) and α1 glycine receptors expressed in Xenopus oocytes. We previously identified specific amino acids of glycine and GABA(A) 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.

Original languageEnglish (US)
Pages (from-to)1199-1205
Number of pages7
JournalMolecular pharmacology
Volume57
Issue number6
StatePublished - 2000

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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