Transgenic expression of a mutant glycine receptor decreases alcohol sensitivity of mice

被引:53
作者
Findlay, GS [1 ]
Wick, MJ [1 ]
Mascia, MP [1 ]
Wallace, D [1 ]
Miller, GW [1 ]
Harris, RA [1 ]
Blednov, YA [1 ]
机构
[1] Univ Texas, Waggoner Ctr Alcohol & Addict Res A4800, Neurobiol Sect, Austin, TX 78712 USA
关键词
D O I
10.1124/jpet.300.2.526
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 alpha(1)(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 alpha(1) subunits in the nervous system was demonstrated using [H-3]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.
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页码:526 / 534
页数:9
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