DBS Mechanisms of Morphine Extinction

DBS 吗啡消退机制

• 批准号: 9750708
• 负责人: Jennifer Luz Barreto Estrada
• 金额: $ 15万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750708
• 关键词: Agonist; Amygdaloid structure; Animal Model; Animals; Area; Behavioral; Biological; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; Cholera Toxin Protomer B; Clinical; Data; Deep Brain Stimulation; Disease; Down-Regulation; Electric Stimulation; Electrodes; Exhibits; Extinction (Psychology); FOS gene; Female; Frequencies; Fright; Future; Hippocampus (Brain); Human; Immunohistochemistry; Impairment; Implantation procedure; Implanted Electrodes; Infusion procedures; Injections; Intervention; Laboratories; Manuscripts; Medial; Mediating; Memory; Mental disorders; Messenger RNA; Methodology; Modeling; Morphine; Movement; Neurons; Neurosurgical Procedures; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus Accumbens; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Physiologic pulse; Play; Prefrontal Cortex; Preparation; Principal Investigator; Procedures; Proteins; Rattus; Refractory; Relapse; Research; Research Personnel; Resistance; Rewards; Role; Signal Transduction; Site; Testing; Tracer; Transcript; Up-Regulation; Ventral Striatum; addiction; anatomical tracing; brain reward regions; cohort; cost; drug seeking behavior; experimental study; learning extinction; nervous system disorder; overexpression; preference; programs; receptor; translational study

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

项目主任/首席调查员(最后、第一、中间)：Barreto-Estrada JL 摘要 吗啡消退的DBS机制 脑深部刺激(DBS)是一种神经外科手术，用于治疗神经学和精神病学 精神错乱。最近在动物和人类身上的研究表明，DBS可能是一种有效的程序 治疗顽固性上瘾。因此，我们建议使用DBS作为治疗大鼠寻求药物行为的方法 模特。我们先前发现腹侧纹状体/伏隔核的高频DBS(HF-DBS) (VS/NAC)减弱吗啡诱导的条件性位置偏爱(CPP)的消退，而低频 DBS(LF-DBS)增强消退记忆(减少寻药行为)。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)基因表达增加。在本研究中，目标1将 研究VS/NAC的LF-DBS是否增加了大脑奖赏回路关键区域的BDNF表达 (即PFC、杏仁核、海马体和VS/NAC)。简而言之，表达吗啡-CPP的大鼠将会灭绝 会话，与低频DBS(20赫兹)一起使用。在灭绝测试日之后，将处死大鼠，并将大脑 收集标本进行Neu-N/BDNF免疫组织化学染色。AIM 1.2将测试一组动物以确定 LF-DBS对雌性大鼠的吗啡戒断有一定的作用。在目标2中，逆行示踪霍乱毒素亚单位 B，与Alexa Fluor-555(CTB)结合，将被注射到VS/NAC并在吗啡/快消光条件下进行测试 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 注射IL)，以确定与吗啡消退相关的脑区之间的连接。在AIM 3.1我们将向IL，ANA-12，一种BDNF受体拮抗剂集中输注，而在Aim 3.2中，全身注射 将进行Trk B受体激动剂7，8DHF的行为学研究，以确定LF-DBS是否消退 增强是通过BDNF信号途径实现的。未来对耐药患者的干预将受益于 LF-DBS后吗啡消失的细胞和行为区域的特征。 OMB编号0925-0001/0002(03/16修订版批准至2018年10月31日)页面续格式页面