DBS Mechanisms of Morphine Extinction

项目主任/主要研究者（最后，第一，中间）：Barreto-Estrada JL 总结 DBS吗啡消退机制 脑深部电刺激（DBS）是一种用于治疗神经和精神疾病的神经外科手术 紊乱最近在动物和人类身上的研究表明，DBS可能是一种有效的手术方法。 治疗顽固性成瘾因此，我们建议使用DBS治疗大鼠的药物寻求行为 模型我们以前发现腹侧纹状体/中脑核的高频DBS（HF-DBS） (VS/NAc）减弱吗啡诱导的条件性位置偏爱（CPP）消退，而低频 DBS（LF-DBS）增强了消退记忆（减少药物寻求行为）。在其他实验中（在 没有DBS），我们证明了表现出良好的吗啡消退率的动物表现出 VS/NAc中脑源性神经营养因子（BDNF）mRNA的增加。在本研究中，目标1将 检查VS/NAc的LF-DBS是否增加脑奖励回路关键区域的BDNF表达 (i.e. PFC、杏仁核、海马和VS/NAc）。简而言之，表达吗啡-CPP的大鼠将接受灭绝， 与LF-DBS（20 Hz）一起使用。在灭绝试验日之后，将处死大鼠，并将脑 收集用于Neu-N/BDNF免疫组织化学。目标1.2将测试一组动物，以确定是否 LF-DBS对雌性大鼠吗啡消退有效。在目标2中，逆行示踪剂霍乱毒素亚单位 将与Alexa Fluor-555（CT B）结合的B注射到VS/NAc中，并在吗啡/快速消退中进行检测 动物这一目标将在没有DBS（2.1-基线）或存在DBS（2.2-示踪剂）的情况下实现 IL中注射）以确定与吗啡消退相关的脑区域之间的连接。在Aim中 3.1我们将集中输注IL，ANA-12，一种BDNF受体拮抗剂，而在Aim 3.2中，全身注射 将进行7，8DHF（一种Trk B受体激动剂），以从行为上确定LF-DBS消退是否 增强由BDNF信号传导介导。治疗抵抗患者的未来干预将受益于 LF-DBS后吗啡消退背后的细胞和行为领域的表征。 OMB编号0925-0001/0002（2016年3月修订版，批准至2018年10月31日）

Program Director/Principal Investigator (Last, First, Middle): Barreto-Estrada JL SUMMARY DBS Mechanisms of Morphine Extinction Deep brain stimulation (DBS) is a neurosurgical procedure that is used to treat neurologic and psychiatric disorders. Recent research in both animals and humans has shown that DBS may be an effective procedure for refractory addiction. We therefore propose to use DBS as treatment for drug-seeking behaviors in a rat model. We previously found that high frequency DBS (HF-DBS) of the ventral striatum/nucleus accumbens (VS/NAc) impaired extinction of morphine-induced conditioned place preference (CPP), whereas low frequency DBS (LF-DBS) enhanced extinction memory (reducing drug seeking behavior). In other experiments (in the absence of DBS), we demonstrated that animals showing good rate of morphine extinction exhibited an increase in brain derived neurotrophic factor (BDNF) mRNA in the VS/NAc. In the present study, Aim 1 will examine whether LF-DBS of the VS/NAc increases BDNF expression in key regions of the brain reward circuit (i.e. PFC, amygdala, hippocampus and VS/NAc). In brief, rats expressing morphine-CPP will receive extinction sessions, together with LF-DBS (20 Hz). After the extinction test day, rats will be sacrificed and brains will be collected for Neu-N/BDNF immunohistochemistry. Aim 1.2 will test a cohort of animals to determine whether LF-DBS is effective in female rats for morphine extinction. In Aim 2, the retrograde tracer cholera toxin subunit B, conjugated to Alexa Fluor-555 (CTB) will be injected in the VS/NAc and tested in Morphine/fast-extinction animals. This aim will be done in the absence of DBS (2.1-baseline) or in the presence of DBS (2.2-tracer injected in IL) to determine the connectivity between brain regions associated with morphine extinction. In Aim 3.1 we will centrally infuse to IL, ANA-12, a BDNF receptor antagonist, while in Aim 3.2, systemic injections of 7,8DHF, a Trk B receptor agonist will be performed to behaviorally determine whether LF-DBS extinction enhancement is mediated by BDNF signaling. Future interventions of treatment-resistant patients will benefit of the characterization of the cellular and behavioral domains underlying morphine extinction after LF-DBS. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page