Mu-opioid receptors in the habenulo-interpeduncular circuit in opioid dependence

项目摘要 戒断是克服阿片类药物依赖和成瘾的主要障碍。识别神经回路 参与和阿片类药物如何调节其活性是开发新的治疗策略所必需的。的 内侧缰核（MHb）表达特别高水平的μ阿片受体（莫尔）， 暗示MHb是阿片类药物戒断和复发的身体和情感症状的热点。 尽管如此，关于莫尔信号传导如何影响MHb投射神经元，或 慢性莫尔信号传导如何诱导MHb回路中的生理变化，从而导致戒断。 MHb神经元主要投射到脚间核（IPN），在那里它们可以释放乙酰胆碱（ACh） 或者谷氨酸盐，有些神经元可以同时释放谷氨酸盐和乙酰胆碱。而胆碱能-和 神经元定义的MHb神经元与成瘾的基础过程有关， 这些共递质的相对重要性仍不清楚。基于先前文献和初步数据 我们认为谷氨酸和乙酰胆碱共同从MHb释放到IPN在介导阿片效应中起重要作用 依赖，包括戒断。在这个探索性的建议中，我们的目标是测试急性和慢性莫尔 激活影响MHb的活性和IPN中的突触传递，并导致阿片依赖性。

PROJECT SUMMARY Withdrawal is a major obstacle in overcoming opioid dependence and addiction. Identifying the neural circuits involved and how opioids modulate their activity is essential for developing new therapeutic strategies. The medial habenula (MHb) expresses particularly high levels of mu-opioid receptor (MOR) and emerging evidence implicates the MHb as a hotspot for the physical and affective symptoms of opioid withdrawal and relapse. Despite this, there is remarkably little information on how MOR signaling influences MHb projection neurons, or how chronic MOR signaling could induce physiological changes in MHb circuits that contribute to withdrawal. MHb neurons project principally to the interpeduncular nucleus (IPN) where they can release acetylcholine (ACh) or glutamate; and some of these neurons can co-release both glutamate and ACh. While cholinergic- and glutamatergic-defined MHb neurons have been implicated in processes underlying addiction, the respective roles and relative importance of these co-transmitters remain unclear. Based on prior literature and preliminary data we posit an important role for glutamate and ACh co-release from MHb to IPN in mediating effects of opioid dependence, including withdrawal. In this exploratory proposal we aim to test how acute and chronic MOR activation influences activity in MHb and synaptic transmission in IPN and contributes to opioid dependence.