Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens.
Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens.
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长期锂治疗可纠正伏隔核中适应不良的多巴胺释放。
DOI：
10.1111/jnc.13769
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发表时间：
2016-11
影响因子：
4.7
通讯作者：
Gould TD
中科院分区：
文献类型：
--
作者：
Can A;Frost DO;Cachope R;Cheer JF;Gould TD
慢性锂治疗可有效减少人类和啮齿动物的躁狂症行为表型。锂发挥这些作用的机制尚不清楚。临床前和临床证据表明，躁狂症患者中脑边缘多巴胺（DA）神经传递增加。我们使用快速扫描循环伏安法来表征急性或慢性锂治疗C57BL6/J小鼠腹侧被盖区（VTA） 20和60 Hz电刺激引起的伏隔核（NAc）核心细胞外DA浓度的变化。慢性锂离子治疗对DA可释放性的影响是通过短脉间训练间隔消耗易释放的DA或急性给予d-安非他明调动易释放的DA来评估的。慢性而非急性锂离子治疗降低了60 Hz脉冲序列刺激后NAc的DA反应幅度。锂处理没有改变DA的释放或再摄取动力学。当使用20或60 Hz脉冲序列每6秒刺激VTA以消耗DA时，慢性治疗不会影响DA反应幅度的逐渐降低。具体来说，与对照小鼠相比，60 Hz脉冲序列的DA反应幅度最初有所降低，但到第五个脉冲序列时，不再有治疗效果。然而，长期锂治疗减弱了d-安非他明诱导的对20hz脉冲序列刺激的DA反应的增加。我们的数据表明，长期服用锂可能通过使NAc VTA轴突末端的易释放DA池正常化来改善躁狂表型。用抗躁狂药物锂治疗三周后，小鼠伏隔核60hz而不是20hz电刺激诱发的多巴胺释放减少，急性安非他明给药后20hz诱发的多巴胺释放增加减弱。这些数据表明，锂可以稳定情绪，因为只有当多巴胺水平异常高时，它才会减弱多巴胺的释放。
Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Preclinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-pulse train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60 Hz pulse train stimulation. Neither lithium treatment altered DA release or reuptake kinetics. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20- or 60 Hz pulse trains, the VTA was stimulated every six seconds to deplete DA. Specifically, the amplitude of DA responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine induced increases in DA responses to 20 Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc. Three weeks’ treatment with the anti-manic drug, lithium, reduced dopamine release in mouse nucleus accumbens evoked by 60 Hz, but not 20 Hz, electrical stimulation of the ventral tegmentum, and attenuated increases in 20 Hz-evoked dopamine release following acute amphetamine administration. These data suggest that lithium stabilizes mood because it attenuates dopamine release only when it is abnormally high.
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