Behavioral characterization of knockin mice with mutations M287L and Q266I in the glycine receptor α1 subunit.
We used behavioral pharmacology to characterize heterozygous knockin mice with mutations (Q266I or M287L) in the α1 subunit of the glycine receptor (GlyR) (J Pharmacol Exp Ther 340:304-316, 2012). These mutations were designed to reduce (M287L) or eliminate (Q266I) ethanol potentiation of GlyR function. We asked which behavioral effects of ethanol would be reduced more in the Q266I mutant than the M287L and found rotarod ataxia to be the behavior that fulfilled this criterion. Compared with controls, the mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. Thus, in addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs.
Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin, TX 78712-0159, USA.
Yuri A
YA
Blednov
Jill M
JM
Benavidez
Gregg E
GE
Homanics
R Adron
RA
Harris
D020001:1-Butanol / Q000494:pharmacology; D000428:Alcohol Drinking / Q000235:genetics; D020270:Alcohol Withdrawal Seizures / Q000175:diagnosis / Q000235:genetics; D019943:Amino Acid Substitution / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003214:Conditioning, Classical; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D005518:Food Preferences / Q000187:drug effects; D055879:Gene Knock-In Techniques; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009048:Motor Skills / Q000187:drug effects; D009154:Mutation / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000494:pharmacology; D011803:Quinine / Q000008:administration & dosage; D018009:Receptors, Glycine / Q000502:physiology*; D057897:Reflex, Righting / Q000187:drug effects / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D045442:Rotarod Performance Test; D012439:Saccharin / Q000008:administration & dosage; D012640:Seizures / Q000139:chemically induced / Q000175:diagnosis; D012727:Sex Characteristics; D013331:Strychnine / Q000494:pharmacology; D055697:Taste Perception / Q000235:genetics
D002492:Central Nervous System Depressants; D018009:Receptors, Glycine; D000431:Ethanol; D016202:N-Methylaspartate; D009538:Nicotine; D020001:1-Butanol; D011803:Quinine; D012439:Saccharin; D013331:Strychnine; D010433:Pentylenetetrazole