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Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition.
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2018-Nov-12 , DOI: 10.1038/s41386-018-0271-x
Caleb J. Browne , Andrew R. Abela , Duong Chu , Zhaoxia Li , Xiaodong Ji , Evelyn K. Lambe , Paul J. Fletcher

The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT terminals in the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.

中文翻译:

背沟纹5-羟色胺神经元通过输入腹侧被盖区而不是伏伏核抑制操作者对报酬的反应:结合光遗传学刺激和5-羟色胺再摄取抑制的研究证据。

单胺神经递质5-羟色胺(5-羟色胺; 5-HT)对动力产生抑制作用,但介导这种作用的回路尚不清楚。在这里,我们使用了光遗传学方法来分离背沟核(DRN)5-HT神经元和中脑边缘多巴胺(DA)系统的5-HT神经支配对小鼠的动机行为。我们发现DRN 5-HT神经元的光遗传学刺激增强了下游5-HT的释放,但这不足以抑制操作员对糖精的反应,糖精是一种有动机的行为。但是,将DRN 5-HT神经元的光遗传刺激与低剂量的选择性5-羟色胺再摄取抑制剂(SSRI)西酞普兰相结合可协同降低手术反应。然后,我们研究了如果光遗传学刺激专门针对中脑边缘DA系统的腹侧被盖区(VTA)或伏隔核(NAc)中的5-HT末端,是否可以概括这些影响。对VTA的5-HT输入的光遗传刺激与西酞普兰治疗相结合,对糖精的响应产生协同降低,类似于以DRN中靶向5-HT神经元产生的变化。但是,当光遗传刺激靶向NAc中的5-HT末端时,未观察到这种效果。综上所述,这些结果表明,DRN 5-HT神经元通过与中枢边缘DA系统在VTA水平上的直接相互作用,对操作者的报酬响应产生抑制作用。
更新日期:2018-11-12
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