Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade
Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade
复制标题
DOI：
10.1073/pnas.0307921101
复制
发表时间：
2004-04-06
影响因子：
11.1
通讯作者：
Caron, MG
中科院分区：
文献类型：
--
作者：
Beaulieu, JM;Sotnikova, TD;Caron, MG
多巴胺（DA）是一种神经递质，参与控制运动，情绪，认知和奖励。已知锂盐给药可通过未知机制抑制实验动物模型中DA相关行为。在这里，我们使用了药物遗传学的方法来表明，DA可以发挥其行为的影响，通过作用于锂敏感的信号级联，涉及Akt/PKB和糖原合成酶激酶3（GSK-3）。在小鼠纹状体中，增加的DA神经传递引起的管理安非他明或缺乏DA转运蛋白的结果在失活Akt和GSK-3 α和GSK-3 β的伴随激活。这些生化变化不受cAMP途径激活的影响，但通过抑制DA合成、D2受体阻断或给予锂盐可有效逆转。此外，GSK-3的药理学或遗传抑制显著降低DA依赖性运动行为。这些数据支持GSK-3作为体内DA和锂作用的重要介体的参与，并表明Akt/GSK-3通路的调节可能与DA相关的疾病相关，例如注意缺陷多动障碍和精神分裂症。
Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3alpha and GSK-3beta. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia.