Behavioural changes produced by transgenic overexpression of gamma2L and gamma2S subunits of the GABAA receptor.
Transgenic mice overexpressing either the mouse gamma2L or gamma2S subunit of the GABAA receptor were generated in a C57BL/6 J x DBA/2 J mixed background and expanded into transgenic lines. Transgenic mice and littermate controls were analysed with respect to altered behaviour indicative of anxiety, motor activity and acute effects of benzodiazepines and alcohol, as well as with regard to altered responses to alcohol withdrawal and acute functional tolerance to alcohol. Biochemical tests assessed flunitrazepam- and ethanol-enhanced 36Cl- flux stimulated by muscimol in cerebellar and cortical microsacs and [3H]-flunitrazepam binding to cerebellar membranes. There were no significant differences in any of these measures between the transgenic and control mice, except in tests of acute functional tolerance to acute injection of ethanol. Compared to controls, mice carrying either the gamma2L or gamma2S transgene developed significantly less tolerance to the ataxic effects of ethanol. We conclude that acute functional tolerance to ethanol is very sensitive to the amount of GABAA receptor gamma2 subunit available (regardless of whether it is gamma2L or gamma2S) but overexpression of neither subunit isoform alters other behavioural and biochemical phenotypes.
Wick
M J
MJ
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Wickm@den-res.org
Radcliffe
R A
RA
Bowers
B J
BJ
Mascia
M P
MP
Lüscher
B
B
Harris
R A
RA
Wehner
J M
JM
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects; D018076:DNA, Complementary; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D011963:Receptors, GABA-A / Q000235:genetics*; D019076:Transgenes / Q000502:physiology; D014316:Tritium
D014151:Anti-Anxiety Agents; D002492:Central Nervous System Depressants; D018076:DNA, Complementary; D011963:Receptors, GABA-A; D014316:Tritium; D000431:Ethanol; D005445:Flunitrazepam