Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression
Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression
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DOI：
10.1016/j.neuropharm.2004.11.015
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发表时间：
2005-03-01
影响因子：
4.7
通讯作者：
McAllister, G
中科院分区：
文献类型：
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作者：
Guscott, M;Bristow, LJ;McAllister, G
几种抗抑郁药和抗精神病药对5-HT 7受体的亲和力及其在中枢神经系统的分布表明其在精神疾病治疗中的潜力。然而，几乎没有直接的证据表明受体在体内的功能来支持这一点。因此，我们通过产生和评估5-HT 7受体敲除小鼠来评估5-HT 7受体作为潜在药物靶标。在5-HT 7受体敲除小鼠和野生型对照之间没有观察到对潜在精神病或焦虑状态敏感的测定的差异。然而，在Porsolt游泳试验中，与对照相比，5-HT 7受体敲除小鼠显示出不动性的显著降低，其表型与抗抑郁剂处理的小鼠相似。有趣的是，用SB-258719（一种选择性5-HT 7受体拮抗剂）治疗野生型并没有显着降低不动性，除非动物在黑暗（或活动）周期而不是光照下进行测试，这增加了大量证据表明昼夜节律对受体功能的影响。下丘脑切片的细胞外记录显示，在5-HT 7受体KO小鼠中，8-OH-DPAT的昼夜节律相移减弱，这也表明受体在昼夜节律调节中的作用。这些药理学和基因敲除研究提供了第一个直接证据，即5-HT 7受体拮抗剂应在抑郁症的治疗中进行疗效研究。(c)2004 Elsevier Ltd.保留所有权利。
The affinity of several antidepressant and antipsychotic drugs for the 5-HT7 receptor and its CNS distribution suggest potential in the treatment of psychiatric diseases. However, there is little direct evidence of receptor function in vivo to support this. We therefore evaluated 5-HT7 receptors as a potential drug target by generating and assessing a 5-HT7 receptor knockout mouse. No difference in assays sensitive to potential psychotic or anxiety states was observed between the 5-HT7 receptor knockout mice and wild type controls. However, in the Porsolt swim test, 5-HT7 receptor knockout mice showed a significant decrease in immobility compared to controls, a phenotype similar to antidepressant treated mice. Intriguingly, treatment of wild types with SB-258719, a selective 5-HT7 receptor antagonist, did not produce a significant decrease in immobility unless animals were tested in the dark (or active) cycle, rather than the light, adding to the body of evidence suggesting a circadian influence on receptor function. Extracellular recordings from hypothalamic slices showed that circadian rhythm phase shifts to 8-OH-DPAT are attenuated in the 5-HT7 receptor KO mice also indicating a role for the receptor in the regulation of circadian rhythms. These pharmacological and genetic knockout studies provide the first direct evidence that 5-HT7 receptor antagonists should be investigated for efficacy in the treatment of depression. (c) 2004 Elsevier Ltd. All rights reserved.