δ-Subunit containing GABAA receptor knockout mice are less sensitive to the actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol

The pharmacological profile of a γ-aminobutyric acid A (GABAA) receptor depends upon subunit composition. Studies using recombinant expression systems suggest that δ-subunit containing GABAA receptors are particularly sensitive to the actions of the GABAA partial agonist, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP, gaboxadol). Here we investigated the actions of THIP in mutant mice lacking the GABAA receptor δ-subunit gene. Using the chloride flux assay, we determined that the actions of THIP were reduced by 21% in the cortical, but not cerebellar, membranes of knockout mice. Similar results were seen with another GABAA agonist, muscimol. Moreover, δ-subunit knockout mice exhibited a 54% reduction in sensitivity to the hypnotic actions of THIP as assessed by the loss of righting reflex test. These data support the notion that δ-containing GABAA receptors are at least partially responsible for the actions of THIP, and contribute to the growing literature suggesting that the pharmacological specificity of GABAA receptors depends on which subunits are present or absent.