Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.
The heterogeneity and distribution of GABA(A) receptor subunits mediates differential roles in behavior. It is thought that particular behavioral responses to benzodiazepine (BZ) ligands might be associated with an action at a regionally defined receptor subtype. However, the role of specific GABA(A) receptor subtypes in particular brain regions is less clear. Such detailed knowledge of regional alpha1-GABA(A) receptor function will advance our understanding of the neural circuitry underlying the role of GABA(A) receptors and the effects of GABA(A)-modulating drugs on behavior. By combining inducible, site-specific alpha1 subunit deletion, using a lentivirus expressing Cre-recombinase in mice with the alpha1 subunit gene flanked by loxP sites, we examine baseline and pharmacological effects of deletion of amygdala alpha1-GABA(A) receptors. We find that amygdala-specific reduction of alpha1 receptor subunits does not affect mRNA or protein levels of amygdala alpha2 or alpha3 subunit receptors. Nor does this inducible reduction affect baseline locomotion or measures of anxiety. However, we also find that this inducible, site-specific deletion does disrupt the normal sedative-locomotor inhibition as well as the anticonvulsive effects, of two distinct BZ-site ligands, diazepam and zolpidem, which is relatively alpha1-subunit selective. These data, using inducible, region and subunit-specific deletion, combined with pharmacogenetic approaches, demonstrate that amygdala expression of the alpha1-GABA(A) receptor subunit is required for normal BZ effects on sedation, locomotion, and seizure inhibition, but not for anxiolysis.
Heldt
Scott A
SA
Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA.
Ressler
Kerry J
KJ
D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects* / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010433:Pentylenetetrazole; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D000077334:Zolpidem
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; C546240:GABRA1 protein, human; C546241:Gabra1 protein, mouse; D006993:Hypnotics and Sedatives; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D049452:Green Fluorescent Proteins; D000077334:Zolpidem; D010433:Pentylenetetrazole