BDNF in the Reward Circuit for DBS-Induced Opioid Extinction

DBS 引起的阿片类药物灭绝的奖赏回路中的 BDNF

• 批准号: 10629686
• 负责人: Jennifer Luz Barreto Estrada
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629686
• 关键词: Amygdaloid structure; Animal Model; Animals; Area; Attenuated; Behavioral; Biological; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; COVID-19 pandemic; Cessation of life; Cholera Toxin; Clinic; Clozapine; Cues; Data; Deep Brain Stimulation; Dorsal; Drug Modelings; Electric Stimulation; Extinction; Frequencies; Future; Genetic; Genetic Techniques; Glutamates; Grant; Hippocampus; Human; Impairment; Implanted Electrodes; Injections; Knowledge; Location; Measures; Medial; Memory; Mental disorders; Molecular; Morphine; Movement Disorders; Neurons; Neurosurgical Procedures; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus Accumbens; Opiate Addiction; Opioid; Overdose; Oxides; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiologic pulse; Pilot Projects; Population; Prefrontal Cortex; Principal Investigator; Procedures; Process; Rattus; Refractory; Relapse; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Rewards; Rodent; Rodent Model; Role; Substance Use Disorder; Time; Ventral Striatum; addiction; antagonist; cocaine overdose; conditioned place preference; cost estimate; designer receptors exclusively activated by designer drugs; drug seeking behavior; drug testing; experimental study; genetic approach; genetic manipulation; immunoreactivity; insight; learning extinction; nervous system disorder; opioid use disorder; pharmacologic; prevent; programs; reduce symptoms; retrograde transport; sobriety; suicidal morbidity; tool

Abstract/Summary 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 previously propose to use DBS as treatment for drug-seeking behaviors in a rat animal model, and 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). Interestingly, we also found that LF-DBS significatively shortens the persistency of the drug (LF-DBS~10 days vs sham-DBS~40 days). At the molecular level, we found that DBS-treated animals increased BDNF expression in the hippocampus (HPC). However, drug reinstatement was not significatively prevented in LF-DBS- treated animals when stimulation was applied only during extinction sessions. In this transition between the SCORE-SuRE grant cycle, we propose to further advance the knowledge in drug- seeking behavior, and in the underlying DBS’ mechanisms of action, by using pharmacological and chemogenetic approaches. Therefore, in the present study, Aim 1a-c will determine whether LF-DBS applied during extinction, in addition to provide electrical stimulation in the phase of drug reinstatement prevents drug seeking in a higher percentage of animals. Also, BDNF expression will be measured in the HPC, as well as in other brain regions, i.e., amygdala, VS/NAc, and medial prefrontal cortex (mPFC). Aim 2a will use a pharmacological approach by infusing BDNF and TrkB antagonist (ANA-12) in the VS/NAc to determine their effects in extinction of morphine CPP. Since glutamatergic neurons in the HPC encompass a subpopulation of neurons expressing BDNF, the approach in Aim 2b is to use the chemogenetic tool, known as designer receptors exclusively activated by designer drugs (DREADDs) to activate HPC glutamatergic neurons in the presence of ANA-12, to prevent extinction of morphine CPP. Activation of DREADDs will be done with clozapine N-oxide (CNO). Aim 2c will inactivate HPC-NAc glutamatergic/BDNFergic projections that will prevent the beneficial effects of LF-DBS. Our study represents a circuit-based approach to better understand the action mechanisms of drug- seeking and extinction. Because rodent models of drug extinction resemble exposure-based therapies in humans, it is possible that targeted electrical stimulation and the DBS-increased expression of pro-extinction molecules might represent an effective future approach to reduce the symptoms of addiction and opioid use disorders (OUD).

摘要/总结 深部脑刺激（DBS）是一种神经外科手术，用于治疗神经系统疾病和 最近对动物和人类的研究表明，DBS 可能会导致精神疾病。 我们之前建议使用 DBS 作为治疗难治性成瘾的有效方法。 针对大鼠动物模型中的药物寻求行为，发现高频 DBS（HF-DBS） 腹侧纹状体/伏隔核（VS/NAc）的吗啡诱导的消退受损 条件性位置偏好（CPP），而低频 DBS（LF-DBS）增强灭绝 记忆力（减少寻药行为），我们还发现LF-DBS。 显着缩短药物的持续时间（LF-DBS~10 天 vs sham-DBS~40 天）。 在分子水平上，我们发现接受 DBS 治疗的动物的 BDNF 表达增加 然而，LF-DBS 并没有显着阻止药物恢复。 仅在经过处理的灭绝过程中施加刺激的动物。 在 SCORE-SuRE 资助周期之间，我们建议进一步推进药物知识 寻找行为，并在 DBS 的潜在作用机制中，通过使用药理学 因此，在本研究中，目标 1a-c 将确定是否 除了在消退阶段提供电刺激外，还在消退期间应用 LF-DBS 此外，恢复药物可以防止较高比例的动物寻求药物。 将在 HPC 以及其他大脑区域（即杏仁核、VS/NAc、 目标 2a 将通过注入药理学方法。 VS/NAc 中的 BDNF 和 TrkB 拮抗剂 (ANA-12) 以确定它们在灭绝中的作用 由于 HPC 中的谷氨酸能神经元包含神经元亚群。 表达 BDNF，Aim 2b 中的方法是使用化学遗传学工具，称为设计器 专门由设计药物 (DREADD) 激活的受体，以激活 HPC 谷氨酸能 ANA-12 存在时，可以阻止吗啡 CPP 的激活。 DREADD 将使用氯氮平 N-氧化物 (CNO) 进行，Aim 2c 将使 HPC-NAc 失活。 谷氨酸/BDNFergic 预测将阻止 LF-DBS 的有益作用。 研究代表了一种基于电路的方法，可以更好地了解药物的作用机制 因为啮齿动物的药物灭绝模型类似于基于暴露的模型。 在人类治疗中，有可能是有针对性的电刺激和 DBS 增加 促灭绝分子的表达可能是未来减少灭绝的有效方法 成瘾和阿片类药物使用障碍 (OUD) 的症状。