Contribution of locus coeruleus-derived galanin to opioid reward and reinforcement

项目摘要 阿片类药物流行已被宣布为国家公共卫生紧急状态。目前的治疗方法有滥用 易感性，仅针对急性过量，和/或对许多阿片成瘾患者无效，以及 迫切需要新的治疗方法。一个有希望的目标是大脑甘丙素系统；减少甘丙素 水平加剧了吗啡的奖赏和戒断，而增加甘丙素则反对阿片类成瘾 行为。然而，这种保护性甘丙素的神经解剖学来源和靶点尚未确定， 甘丙肽对阿片类药物自愿摄取的影响尚未被调查。蓝斑(LC) 调节中脑边缘奖赏通路的活性，并与阿片成瘾有关，以及 该核团中80%的去甲肾上腺素能神经元共表达甘丙素。我们已经组装了一套基因上的 改变缺乏或过度表达去甲肾上腺素能神经元甘丙素的小鼠来验证这一假说 LC来源的甘丙素抑制阿片类药物抑制腹侧多巴胺(DA)神经元的能力 被盖区(VTA)和减弱阿片类药物奖励/强化，以及以自分泌方式作用于 预防LC多动，减少戒断症状。在目标1中，我们将使用原位杂交来 测定VTA、切片和体内甘丙肽受体表达细胞的神经化学特性 电生理学：研究甘丙素的电路和细胞机制。 对抗阿片类药物诱导的VTA DA神经元活动。在目标2中，我们将使用上述转基因小鼠 使用操作剂静脉注射来测试LC衍生的甘丙素抑制阿片类药物强化的假设。阿片类自我 管理范式。在目标3中，我们将评估甘丙肽抑制LC细胞过度活动的能力。 阿片类药物戒断时的可塑性和厌恶症状。这些目标的实现将奠定基础 以LC/Galanin为基础的阿片成瘾治疗。

Project Summary The opioid epidemic has been declared a national public health emergency. Current treatments have abuse liability, target acute overdose only, and/or are ineffective for many people suffering from opioid addiction, and new therapies are desperately needed. One promising target is the brain galanin system; reducing galanin levels exacerbates morphine reward and withdrawal, while increasing galanin opposes opioid addiction-like behaviors. However, the neuroanatomical source and target of this protective galanin have not been identified, and the effects of galanin on voluntary opioid intake have not been investigated. The locus coeruleus (LC) modulates the activity of the mesolimbic reward pathway and has been implicated in opioid addiction, and 80% of noradrenergic neurons in this nucleus co-express galanin. We have assembled a set of genetically altered mice that either lack or overexpress galanin specifically in noradrenergic neurons to test the hypothesis that LC-derived galanin suppresses the ability of opioids to disinhibit dopamine (DA) neurons in the ventral tegmental area (VTA) and attenuates opioid reward/reinforcement, as well as acts in an autocrine manner to prevent LC hyperactivity and reduces withdrawal symptoms. In Aim 1, we will use in situ hybridization to determine the neurochemical identity of galanin receptor-expressing cells in the VTA, and slice and in vivo electrophysiology to investigate the circuitry and cellular mechanisms underlying the ability of galanin to oppose opioid-induced VTA DA neuron activity. In Aim 2, we will use the transgenic mice described above to test the hypothesis that LC-derived galanin inhibits opioid reinforcement using an operant i.v. opioid self- administration paradigm. In Aim 3, we will assess the ability of galanin to suppress LC hyperactivity, cellular plasticity, and aversive symptoms during opioid withdrawal. Completion of these aims will lay the groundwork for LC/galanin-based therapies for opioid addiction.