Noradrenergic Plasticity in Opioid Withdrawal

项目摘要 美国的阿片类药物流行是深刻的，每年的经济负担为958亿美元 (2016自2001年以来，总成本超过100亿美元。此外，药物过量现在是第一个原因， 2017年有超过72，000人死于意外死亡，阿片类药物过量占这些死亡的60%以上。 为了开发治疗阿片类药物使用障碍（OUD）的药物和行为疗法， 了解阿片类药物使用和戒断后发生的神经回路和神经适应。障碍 在情感谱上的表现往往是高共患病率。因此，必须了解阿片类药物如何 改变调节成瘾样行为，厌恶/焦虑和 对压力反应。在延伸杏仁核的一个节点，终纹床核（BNST），接收 大脑中去甲肾上腺素（NE，一种应激反应神经递质）的去神经支配。BNST是 阿片类药物戒断行为的主要贡献者，以前，我们证明了吗啡暴露和 戒断调节大鼠BNST NE释放和摄取机制。我们的初步数据表明， 慢性应激增强了相同的去甲肾上腺素能回路小鼠，阿片类药物暴露和戒断 调节NE神经元。此外，在小鼠中，我们观察到性别特异性的急性戒断行为，戒断 导致睡眠节律紊乱，以及长期禁欲的焦虑样行为。BNST是一种性 双形脑区，我们观察到进一步的性别差异（和一些相似之处）在BNST生理。 有趣的是，我们的数据表明，在选择回路中， 阿片类药物戒断，这可能最终改变BNST输出到经典的奖励电路。这些数据告诉我们， 我们的建议的中心假设调查了3个目标：阿片类药物戒断1。增强了突触驱动， NE神经元支配BNST，2。促进BNST内增强的去甲肾上腺素能传递，和3. 在BNST内诱导神经元可塑性，增强阿片类戒断综合征相关行为。

PROJECT SUMMARY The opioid epidemic in the United States is profound, with an annual economic burden of $95.8 billion dollars (2016 dollars) and a total cost of over $1Trillion since 2001. Moreover, drug overdose is now the no. 1 cause of accidental death with over 72,000 lives lost in 2017, and opioid overdoses account for over 60% of these deaths. In order to develop pharmacological and behavioral therapies to treat opioid use disorder (OUD), it is important to understand the neural circuitry and neuroadaptation that occurs following opioid use and withdrawal. Disorders on the affective spectrum often exhibit high comorbidity. Therefore, it is imperative to understand how opioids alter critical circuits and neurotransmitters that regulate addiction-like behaviors, aversion/anxiety and the response to stress. A node in the extended amygdala, the bed nucleus of the stria terminalis (BNST), receives the densest innervation of norepinephrine (NE, a stress responsive neurotransmitter) in the brain. The BNST is a major contributor to opioid withdrawal behaviors and previously, we demonstrated that morphine exposure and withdrawal modulates BNST NE release and uptake mechanisms in rats. Our preliminary data demonstrate that chronic stress enhances the same noradrenergic circuitry mice, and that opioid exposure and withdrawal modulates NE neurons. Furthermore, in mice we observe sex specific acute withdrawal behaviors, withdrawal induced disruption of sleep rhythms, and anxiety-like behavior in protracted abstinence. The BNST is a sexually dimorphic brain region, and we observe further sex differences in (and some similarities) in BNST physiology. Intriguingly, our data suggest that there may be reductions in excitatory transmission in select circuitry following opioid withdrawal, which may ultimately alter BNST output to classical reward circuits. These data inform the central hypothesis of our proposal investigated in 3 aims: opioid withdrawal 1. enhances the synaptic drive onto NE neurons innervating the BNST, 2. facilitates enhanced noradrenergic transmission within the BNST, and 3. induces glutamatergic plasticity within the BNST intensifying opioid withdrawal syndrome related behaviors.