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.

中文翻译：

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学会避免需要VTA KOR介导的多巴胺减少。

从厌恶经历中正确学习对于生存至关重要，但它在许多精神疾病以及多巴胺能神经退行性疾病中都是异常的过程。虽然已知中脑边缘的多巴胺系统对于奖励学习至关重要，但引导回避的潜在多巴胺信号传导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有害的。理想的位置是腹侧被盖区（VTA）KOR，以直接塑造多巴胺信号转导引起的厌恶感减少，但很少考虑它们在这一过程中的作用。为了确定VTA KOR活性在调节多巴胺信号传导和回避中的必要性，我们测试了VTA KOR阻断对雄性Sprague-Dawley大鼠对厌恶刺激的实时多巴胺能反应的影响，并了解了回避。我们发现，对VTA KOR的阻滞减弱了厌恶引起的多巴胺减少，并且这种治疗也避免了厌恶经历后的回避。为了确定是否需要避免避免纹状体多巴胺引起的减少，我们在伏伏核内D2受体激动剂治疗后测试了避免行为。