Glycine and γ-Aminobutyric AcidA Receptor Function Is Enhanced by Inhaled Drugs of Abuse
- 1Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina (M.J.B., J.L.W., S.J.M.); and 2Department of Anesthesia, University of California, San Francisco, California (E.I.E., D.H.G.)
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)Areceptor-mediated synaptic currents in rat hippocampal slices. All three inhalants significantly and reversibly enhanced neurotransmitter-activated currents at α1β1 GABAA and α1 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.
Footnotes
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Send reprint requests to: S. John Mihic, Ph.D., Section of Neurobiology, School of Biological Sciences, 2500 Speedway, University of Texas at Austin, Austin, TX 78712-1095.
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M.J.B. was supported by a predoctoral training grant from the National Institute on Alcohol Abuse and Alcoholism. This work was supported by National Institute on Alcohol Abuse and Alcoholism Grants AA11525 (S.J.M.) and AA12251 (J.L.W.) and National Institute of General Medical Sciences Grant GM47818 (E.I.E.).
- Abbreviations:
- TOL
- toluene
- CNS
- central nervous system
- GABA
- γ-aminobutyric acid
- Gly-R
- glycine receptor
- IPSC
- inhibitory postsynaptic current
- MBS
- modified Barth's saline
- NMDA
- N-methyl-d-aspartate
- TCE
- 1,1,1-trichloroethane
- TCY
- trichloroethylene
- TM2
- transmembrane domain 2
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- Received August 25, 1999.
- Accepted February 29, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
