Amygdala-Specific Reduction of alpha 1-GABA(A) Receptors Disrupts the Anticonvulsant, Locomotor, and Sedative, But Not Anxiolytic, Effects of Benzodiazepines in Mice

作者：Heldt Scott A; Ressler Kerry J^*

来源：Journal of Neuroscience, 2010, 30(21): 7139-7151.

DOI：10.1523/JNEUROSCI.0693-10.2010

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 alpha 1-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 alpha 1 subunit deletion, using a lentivirus expressing Cre-recombinase in mice with the alpha 1 subunit gene flanked by loxP sites, we examine baseline and pharmacological effects of deletion of amygdala alpha 1-GABA(A) receptors. We find that amygdala-specific reduction of alpha 1 receptor subunits does not affect mRNA or protein levels of amygdala alpha 2 or alpha 3 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 alpha 1-subunit selective. These data, using inducible, region and subunit-specific deletion, combined with pharmacogenetic approaches, demonstrate that amygdala expression of the alpha 1-GABA(A) receptor subunit is required for normal BZ effects on sedation, locomotion, and seizure inhibition, but not for anxiolysis.

• 出版日期2010-5-26