Division of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, New York 10032, USA.
J Neurosci. 2011 Nov 2;31(44):15742-50. doi: 10.1523/JNEUROSCI.2989-11.2011.
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.
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，但响应率较低，副作用常常导致停药。副作用谱表明 SSRIs 抑制多巴胺能活性，但机制洞察力仍然很少。在这里，我们表明在成年期而非发育期慢性 5-HT 转运体（5-HTT）阻断以剂量依赖和可逆的方式损害基底神经节依赖的行为。此外，慢性 5-HTT 阻断减少纹状体多巴胺（DA）含量和代谢。通过 L-DOPA 给药逆转行为缺陷表明，减少的 DA 信号与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 信号会降低副作用并提高基于 SSRI 的治疗的疗效。
