GABAA receptors containing ρ1 subunits contribute to in vivo effects of ethanol in mice.
GABAA receptors consisting of ρ1, ρ2, or ρ3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ρ1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ρ subunit genes with alcohol dependence. We determined if genetic deletion of ρ1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, ρ1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of ρ1 did not change expression of ρ2, α2, or α6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ1" antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ρ1 null mice (LORR and rotarod tests), but the ρ1 antagonist did not produce these effects in ρ1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid ("ρ2" antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ρ1 that were opposite of the effects of deleting (or inhibiting) ρ1. These results suggest that ρ1 has a predominant role in two in vivo effects of ethanol, and a role for ρ2 may be revealed when ρ1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ρ1 and ρ2 receptors. These data indicate that ethanol action on GABAA receptors containing ρ1/ρ2 subunits may be important for specific effects of ethanol in vivo.
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Yuri A
YA
Blednov
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Jillian M
JM
Benavidez
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Mendy
M
Black
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Courtney R
CR
Leiter
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Elizabeth
E
Osterndorff-Kahanek
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
David
D
Johnson
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
Cecilia M
CM
Borghese
Faculty of Pharmacy, The University of Sydney, Sydney NSW, Australia.
Jane R
JR
Hanrahan
Department of Pharmacology, The University of Sydney, Sydney NSW, Australia.
Graham A R
GA
Johnston
Faculty of Pharmacy, The University of Sydney, Sydney NSW, Australia.
Mary
M
Chebib
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, United States of America.
R Adron
RA
Harris
D000818:Animals; D001007:Anxiety / Q000523:psychology; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology*; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D010721:Phosphinic Acids / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D045442:Rotarod Performance Test; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002492:Central Nervous System Depressants; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; C547869:Gabrr1 protein, mouse; D010721:Phosphinic Acids; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D007649:Ketamine