Abstract
Glycine receptors (GlyRs) are pentameric ligand-gated ion channels that inhibit neurotransmission in the adult brainstem and spinal cord. GlyR function is potentiated by ethanol in vitro, and a mutant GlyR subunit α1(S267Q) is insensitive to the potentiating effects of ethanol. To test the importance of GlyR for the actions of ethanol in vivo, we constructed transgenic mice with this mutation. Under the control of synapsin I regulatory sequences, transgenic expression of S267Q mutant GlyR α1 subunits in the nervous system was demonstrated using [3H]strychnine binding and immunoblotting. These mice showed decreased sensitivity to ethanol in three behavioral tests: ethanol inhibition of strychnine seizures, motor incoordination (rotarod), and loss of righting reflex. There was no change in ethanol sensitivity in tests of acute functional tolerance or body temperature, and there was no change in ethanol metabolism. Transgene effects were pharmacologically specific for ethanol, compared with pentobarbital, flurazepam, and ketamine. These results support the idea that glycine receptors contribute to some behavioral actions of ethanol and that ethanol sensitivity can be changed in vivo by transgenic expression of a single receptor subunit.
Footnotes
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↵1 Current address: Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, CO 80282.
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↵2 Current address: Consiglio Nazionale delle Ricerche, Dip. Di Biologia Sperimentale (Sezione di Neuroscienze), Cittadella Universitaria, SS 554 (Km 4.500), 09042 Monserrato, Cagliari, Italy.
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This study was supported by funds from National Institutes of Health (AA06399 and GM47818) and Texas Commission on Alcohol and Drug Addiction.
- Abbreviations:
- GABA
- γ-aminobutyric acid
- GlyR
- glycine receptor
- LORR
- loss of righting reflex
- Syn
- rat synapsin I
- BEC
- blood ethanol concentration
- spdot− mice
- heterozygous C57BL/6J-Glra1spd–ot mice
- Received September 6, 2001.
- Accepted October 29, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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