Boehm Stephen L, Homanics Gregg E, Blednov Yuri A, Harris R Adron
Department of Psychology, State University of New York at Binghamton, 13902, USA.
Eur J Pharmacol. 2006 Jul 17;541(3):158-62. doi: 10.1016/j.ejphar.2006.02.054. Epub 2006 May 17.
The pharmacological profile of a gamma-aminobutyric acid A (GABA(A)) receptor depends upon subunit composition. Studies using recombinant expression systems suggest that delta-subunit containing GABA(A) receptors are particularly sensitive to the actions of the GABA(A) 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 GABA(A) receptor delta-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 GABA(A) agonist, muscimol. Moreover, delta-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 delta-containing GABA(A) receptors are at least partially responsible for the actions of THIP, and contribute to the growing literature suggesting that the pharmacological specificity of GABA(A) receptors depends on which subunits are present or absent.
γ-氨基丁酸A（GABA(A)）受体的药理学特性取决于亚基组成。使用重组表达系统的研究表明，含有δ亚基的GABA(A)受体对GABA(A)部分激动剂4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇（THIP，加波沙朵）的作用特别敏感。在此，我们研究了THIP在缺乏GABA(A)受体δ亚基基因的突变小鼠中的作用。使用氯离子通量测定法，我们确定在基因敲除小鼠的皮质而非小脑膜中，THIP的作用降低了21%。另一种GABA(A)激动剂蝇蕈醇也得到了类似结果。此外，通过翻正反射测试评估，δ亚基基因敲除小鼠对THIP催眠作用的敏感性降低了54%。这些数据支持了这样一种观点，即含有δ亚基的GABA(A)受体至少部分地介导了THIP作用，并且这也有助于越来越多的文献表明GABA(A)受体的药理学特异性取决于哪些亚基存在或缺失。
