Dept. Biomedical Sciences, Marquette University, 561 N. 15th St SC 446, Milwaukee, WI, 53233, USA.
Dept. Biomedical Sciences, Marquette University, 561 N. 15th St SC 446, Milwaukee, WI, 53233, USA.
Neuropharmacology. 2020 May 1;167:107996. doi: 10.1016/j.neuropharm.2020.107996. Epub 2020 Feb 11.
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.
从厌恶体验中进行适当的学习对于生存至关重要，但在广泛的精神障碍以及多巴胺能神经退行性疾病中，这是一种异常的过程。虽然中脑边缘多巴胺系统对于奖励学习至关重要，但指导回避的潜在多巴胺信号模式的特征仍然未知。厌恶刺激可能通过内啡肽/κ 阿片受体（KOR）系统直接调节多巴胺信号，因为κ阿片受体在这个神经回路中表达，其激活在啮齿动物和人类中都是厌恶的。腹侧被盖区（VTA）的 KOR 处于直接影响回避引起的多巴胺信号减少的理想位置，但它们在这个过程中的作用很少被考虑。为了确定 VTA KOR 活性在调节多巴胺信号和回避中的必要性，我们测试了 VTA KOR 阻断对雄性 Sprague-Dawley 大鼠回避体验中实时多巴胺反应和习得回避的影响。我们发现 VTA KOR 阻断减弱了回避引起的多巴胺减少，并且这种治疗还防止了回避体验后的回避。为了确定纹状体多巴胺的回避诱导减少是否是回避所必需的，我们测试了在核内伏隔核 D2 受体激动剂治疗后的回避。这种治疗也防止了回避，并且与回避诱导的多巴胺减少降低高亲和力 D2 受体的多巴胺信号并抑制回避敏感的纹状体输出回路以促进回避的观点一致。
