Learned avoidance requires VTA KOR-mediated reductions in dopamine.
Learned avoidance requires VTA KOR-mediated reductions in dopamine.
复制标题
习得性回避需要 VTA KOR 介导的多巴胺减少。
DOI：
10.1016/j.neuropharm.2020.107996
复制
发表时间：
2020
影响因子：
4.7
通讯作者：
Wheeler,RobertA
中科院分区：
文献类型：
--
作者：
Robble,MykelA;Bozsik,MaryE;Wheeler,DanielS;Wheeler,RobertA
从厌恶的经历中正确地学习对于生存是必不可少的，然而这在广泛的精神障碍中是一个异常的过程，多巴胺能神经退行性疾病也是如此。虽然已知中脑边缘多巴胺系统对于奖赏学习是必不可少的，但是指导回避的多巴胺信号传导的潜在模式的特征仍然未知。厌恶性刺激可以通过强啡肽/κ阿片受体（KOR）系统直接调节多巴胺信号传导，因为κ阿片受体在该神经回路中表达，并且它们的激活在啮齿动物和人类中都是厌恶性的。中脑被盖区（VTA）KOR的理想定位是直接塑造厌恶诱导的多巴胺信号减少，但他们在这一过程中的作用很少得到考虑。为了确定VTA KOR活性在多巴胺信号传导和回避调节中的必要性，我们测试了VTA KOR阻断对雄性Sprague-Dawley大鼠对厌恶刺激和学习性回避的真实的多巴胺能反应的影响。我们发现，VTA KOR的阻断减弱了厌恶引起的多巴胺减少，这种治疗也防止了厌恶体验后的回避。为了确定是否厌恶引起的纹状体多巴胺的减少是必要的回避，我们测试了回避后的治疗与内核多巴胺D2受体激动剂。这种治疗也防止了回避，并且与以下观点一致，即厌恶诱导的多巴胺减少了高亲和力D2受体处的多巴胺信号传导，并解除了对厌恶敏感的纹状体输出回路的抑制，以促进回避。
Proper learning from an aversive experience is essential for survival, yet it is an aberrant process in a wide range of mental disorders, as well as dopaminergic neurodegenerative disease. While the mesolimbic dopamine system is known to be essential for reward learning, the characterization of a potential pattern of dopamine signaling that guides avoidance remains unknown. Aversive stimuli may directly modulate dopamine signaling through the dynorphin/kappa opioid receptor (KOR) system, as kappa opioid receptors are expressed in this neural circuit and their activation is aversive in both rodents and humans. Ventral tegmental area (VTA) KORs are ideally positioned to directly shape aversion-induced reductions in dopamine signaling, but their role in this process has received little consideration. To determine the necessity of VTA KOR activity in the regulation of dopamine signaling and avoidance, we tested the effects of VTA KOR blockade on real time dopaminergic responses to aversive stimuli and learned avoidance in male Sprague-Dawley rats. We found that blockade of VTA KORs attenuated aversion-induced reductions in dopamine, and this treatment also prevented avoidance following the aversive experience. To determine whether aversion-induced reductions in striatal dopamine are necessary for avoidance, we tested avoidance following treatment with an intra nucleus accumbens D2 receptor agonist. This treatment also prevented avoidance and is consistent with the view that aversion-induced reductions in dopamine reduce dopamine signaling at high affinity D2 receptors and disinhibit an aversion-sensitive striatal output circuit to promote avoidance.