Klein Michael T, Teitler Milt
Center for Neuropharmacology & Neuroscience, Albany Medical College, Albany, New York 12208, USA.
J Neurochem. 2009 Apr;109(1):268-74. doi: 10.1111/j.1471-4159.2009.05958.x. Epub 2009 Feb 5.
Recent studies have indicated that the serotonin [5-hydroxytryptamine (5-HT)] 1E receptor, originally discovered in human brain tissue, is not expressed in rat or mouse brain. Thus, there have been few reports on 5-HT(1E) receptor drug development. However, expression of 5-HT(1E) receptor mRNA has been shown in guinea pig brain. To establish this species as an animal model for 5-HT(1E) drug development, we identified brain regions that exhibit 5-carboxyamidotryptamine, ritanserin, and LY344864 - insensitive [(3)H]5-HT binding (characteristic of the 5-HT(1E) receptor). In hippocampal homogenates, where 5-HT(1E) receptor density was sufficiently high for radioligand binding analysis, 100 nM 5-carboxyamidotryptamine, 30 nM ritanserin, and 100 nM LY344864 were used to mask [(3)H]5-HT binding at non-5-HT(1E) receptors. The K(d) of [(3)H]5-HT was 5.7 +/- 0.7 nM and is indistinguishable from the cloned receptor K(d) of 6.5 +/- 0.6 nM. The affinities of 16 drugs for the cloned and hippocampal-expressed guinea pig 5-HT(1E) receptors are essentially identical (R(2) = 0.97). These findings indicate that using these conditions autoradiographical distribution and signal transduction studies of the 5-HT(1E) receptor in guinea pig brain are feasible. Using the guinea pig as an animal model should provide important insights into possible functions of this receptor and the therapeutic potential of selective human 5-HT(1E) drugs.
最近的研究表明，最初在人类脑组织中发现的5-羟色胺（5-羟色胺，5-HT）1E受体在大鼠或小鼠脑中不表达。因此，关于5-HT（1E）受体药物开发的报道很少。然而，5-HT（1E）受体mRNA已在豚鼠脑中显示表达。为了将该物种确立为5-HT（1E）药物开发的动物模型，我们确定了表现出对5-羧酰胺色胺、利坦色林和LY344864不敏感的[（3）H]5-HT结合（5-HT（1E）受体的特征）的脑区。在海马匀浆中，5-HT（1E）受体密度足够高，可用于放射性配体结合分析，使用100 nM 5-羧酰胺色胺、30 nM利坦色林和100 nM LY344864来掩盖非5-HT（1E）受体处的[（3）H]5-HT结合。[（3）H]5-HT的K（d）为5.7±0.7 nM，与克隆受体的K（d）6.5±0.6 nM无差异。16种药物对克隆的和海马表达的豚鼠5-HT（1E）受体的亲和力基本相同（R（2）=0.97）。这些发现表明，使用这些条件对豚鼠脑中5-HT（1E）受体进行放射自显影分布和信号转导研究是可行的。将豚鼠用作动物模型应该能够为该受体的可能功能以及选择性人类5-HT（1E）药物的治疗潜力提供重要见解。
