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

项目总监/首席研究员（最后、第一、中间）：Barreto-Estrada JL 概括 DBS 吗啡消退机制 深部脑刺激（DBS）是一种神经外科手术，用于治疗神经和精神疾病 失调。最近对动物和人类的研究表明 DBS 可能是一种有效的治疗方法 对于难治性成瘾。因此，我们建议使用 DBS 作为大鼠寻药行为的治疗方法 模型。我们之前发现腹侧纹状体/伏核的高频 DBS (HF-DBS) (VS/NAc) 吗啡诱导的条件性位置偏好 (CPP) 消退受损，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 缺乏 DBS），我们证明表现出良好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 增加。在本研究中，目标 1 将 检查 VS/NAc 的 LF-DBS 是否会增加大脑奖励回路关键区域的 BDNF 表达 （即 PFC、杏仁核、海马体和 VS/NAc）。简而言之，表达吗啡-CPP 的老鼠将会灭绝 会话，以及 LF-DBS (20 Hz)。灭绝测试日后，将处死老鼠并取出大脑 收集用于 Neu-N/BDNF 免疫组织化学分析。目标 1.2 将测试一组动物以确定是否 LF-DBS 对雌性大鼠有效吗啡灭绝。在目标 2 中，逆行示踪霍乱毒素亚基 B，与 Alexa Fluor-555 (CTB) 结合的物质将被注射到 VS/NAc 中并在吗啡/快速消光中进行测试 动物。该目标将在没有 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大脑区域之间的连接性。瞄准 3.1我们将集中输注IL，ANA-12，一种BDNF受体拮抗剂，而在目标3.2中，全身注射 7,8DHF，一种 Trk B 受体激动剂，将进行行为学测定 LF-DBS 是否消退 增强是由 BDNF 信号传导介导的。未来对治疗耐药患者的干预措施将受益于 LF-DBS 后吗啡消退的细胞和行为域的特征。 OMB 编号 0925-0001/0002（修订版 03/16 已批准至 10/31/2018） 页面延续格式页面