Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo.
Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo.
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DOI：
10.1007/s00213-009-1521-8
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发表时间：
2009-07
影响因子：
3.4
通讯作者：
Roth, Bryan L.
中科院分区：
文献类型：
--
作者：
Abbas, Atheir I.;Hedlund, Peter B.;Huang, Xi-Ping;Tran, Thuy B.;Meltzer, Herbert Y.;Roth, Bryan L.
氨磺必利在许多欧洲国家被批准用于治疗精神分裂症的临床用途，在意大利也被批准用于治疗心境恶劣，一种轻度抑郁症。氨磺必利在许多临床试验中也被证明是一种用于重度抑郁症患者的抗抑郁药。部分由于氨磺必利的选择性D2/D3受体拮抗剂特性，长期以来人们普遍认为多巴胺能调节是负责介导其抗抑郁和抗精神病特性的近端事件。这些研究的目的是确定氨磺必利的抗抑郁作用是否通过与其他受体的脱靶相互作用介导。我们进行了以下实验：（1）检查了氨磺必利在大量CNS分子靶点的药理学特征，（2）在发现对人5-HT 7 a 5-羟色胺受体的高效拮抗剂亲和力后，表征了氨磺必利作为抗抑郁药在野生型和5-HT 7受体敲除小鼠中的作用。我们发现氨磺必利是5-HT 7a受体的有效竞争性拮抗剂，与此处研究的其他分子靶点的相互作用可以解释其体内抗抑郁作用。值得注意的是，与野生型同窝出生小鼠相比，5-HT 7受体敲除小鼠在广泛使用的啮齿动物抑郁模型（悬尾试验）中对氨磺必利无反应。这些结果表明，5-HT 7a受体拮抗作用，而不是D2/D3受体拮抗作用，可能是氨磺必利抗抑郁作用的基础。
Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties. The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors. We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of CNS molecular targets and (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knock-out mice. We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated here could explain its antidepressant actions in vivo. Significantly, and in contrast to their wildtype littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in a widely used rodent model of depression, the tail suspension test. These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.
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影响因子：
7.6
作者：
Jensen, Niels H.;Rodriguiz, Ramona M.;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
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作者：
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作者：
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