Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.
Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.
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DOI：
10.1111/j.1471-4159.2012.07739.x
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发表时间：
2012-06
影响因子：
4.7
通讯作者：
Kuhn DM
中科院分区：
文献类型：
--
作者：
Angoa-Pérez M;Kane MJ;Briggs DI;Sykes CE;Shah MM;Francescutti DM;Rosenberg DR;Thomas DM;Kuhn DM
以行为去抑制为特征的神经精神障碍，包括强迫性障碍（例如，强迫症; OCD）和冲动控制（例如，冲动性攻击），是严重的，非常普遍和慢性致残。这些疾病的治疗选择非常有限。行为去抑制障碍的病理生理学基础知之甚少，但有人认为5-羟色胺功能障碍可能起作用。缺乏编码脑色氨酸羟化酶2（Tph 2 −/−）的基因的小鼠，在合成5-羟色胺的初始和限速酶中，在许多行为测定中进行了测试，这些测定因其在模拟人类神经精神疾病中的实用性而闻名。缺乏Tph 2（和大脑5 HT）的小鼠表现出强烈的强迫和冲动行为，包括极端的攻击性。冲动是运动的形式，而不是认知的，因为Tph 2 −/−小鼠在空间学习任务中表现出正常的获得和反向学习。通过用其直接前体5-羟色氨酸治疗Tph 2 −/−小鼠来恢复5-HT水平，可以减弱强迫和冲动攻击行为。令人惊讶的是，在Tph 2 −/−小鼠中，缺乏5 HT与焦虑样行为无关。结果表明，5-HT介导的行为抑制解除在哺乳动物的大脑独立的焦虑。
Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g., obsessive-compulsive disorder; OCD) and impulse-control (e.g., impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2−/−), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2−/− mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2−/− mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2−/− mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.
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影响因子：
64.8
作者：
Liu, Yan;Jiang, Yun'ai;Si, Yunxia;Kim, Ji-Young;Chen, Zhou-Feng;Rao, Yi
通讯作者：
Rao, Yi
DOI：
10.1073/pnas.0810793106
发表时间：
2009-06-23
影响因子：
11.1
作者：
Alenina, Natalia;Kikic, Dana;Bader, Michael
通讯作者：
Bader, Michael
影响因子：
5.3
作者：
Miyazaki, Katsuhiko;Miyazaki, Kayoko W.;Doya, Kenji
通讯作者：
Doya, Kenji
影响因子：
64.8
作者：
Collins, Pamela Y.;Patel, Vikram;Joestl, Sarah S.;March, Dana;Insel, Thomas R.;Daar, Abdallah S.
通讯作者：
Daar, Abdallah S.
影响因子：
64.8
作者：
NELSON, RJ;DEMAS, GE;SNYDER, SH
通讯作者：
SNYDER, SH