Noradrenergic Plasticity in Opioid Withdrawal

项目总结 美国阿片类药物泛滥影响深远，每年造成958亿美元的经济负担 (2016美元)，自2001年以来总成本超过1万亿美元。此外，吸毒过量现在是导致 2017年意外死亡超过7.2万人，阿片类药物过量占死亡人数的60%以上。 为了开发治疗阿片类药物使用障碍的药物和行为疗法，这一点很重要。 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。精神障碍 在情感谱系上往往表现出高度的共病。因此，必须了解阿片类药物是如何 改变调控成瘾类行为、厌恶/焦虑和 对压力的反应。延伸的杏仁核中的一个节点，终纹床核(BNST)，接收 大脑中最密集的去甲肾上腺素(NE，一种应激反应神经递质)神经支配。BNST是 阿片类药物戒断行为的一个主要因素，在此之前，我们证明了吗啡暴露和 戒断对大鼠BNST-NE释放和摄取机制的调节我们的初步数据表明 慢性应激增强了同样的去甲肾上腺素能回路，阿片类药物的暴露和戒断 调节去甲肾上腺素神经元。此外，在小鼠身上，我们观察到特定性别的急性戒断行为、戒断 导致长期禁欲的睡眠节律被打乱，以及焦虑样行为。BNST是一个性爱的 我们观察到BNST生理上的进一步性别差异(和一些相似之处)。 有趣的是，我们的数据表明，在以下选择电路中，兴奋性传递可能会减少 阿片类药物的戒断，最终可能改变BNST对经典奖赏回路的输出。这些数据将向 我们建议的中心假说有三个目的：阿片类药物戒断：1.增强突触驱动 支配BNST的NE神经元，2.促进BNST内去甲肾上腺素能传递的增强，以及3. 诱导BNST内谷氨酸能可塑性，加强阿片类药物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.