Chronic 5-HT Transporter Blockade Reduces DA Signaling to Elicit Basal Ganglia Dysfunction
Chronic 5-HT Transporter Blockade Reduces DA Signaling to Elicit Basal Ganglia Dysfunction
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DOI：
10.1523/jneurosci.2989-11.2011
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发表时间：
2011-11-02
影响因子：
5.3
通讯作者：
Ansorge, Mark S.
中科院分区：
文献类型：
--
作者：
Morelli, Emanuela;Moore, Holly;Ansorge, Mark S.
5-羟色胺（5-HT）选择性再摄取抑制剂（SSRIs）被广泛用于治疗抑郁症、焦虑症和其他神经精神疾病，但反应率很低，而且副作用经常导致停药。副作用分析表明，SSRIs抑制多巴胺能活性，但机制的见解仍然很少。本研究表明，在小鼠中，慢性5-羟色胺转运体（5-羟色胺转运体，5-羟色胺转运体）阻断在成年期而非发育期间以剂量依赖性和可逆性的方式损害基底神经节依赖行为。此外，慢性5-HTT阻断降低纹状体多巴胺（DA）含量和代谢。通过左旋多巴治疗行为缺陷的逆转表明，减少的DA信号和受损的基底神经节依赖行为之间存在因果关系。我们的数据表明，增强DA信号可以减少副作用，提高以ssri为基础的治疗的疗效。
Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy.