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/概要 脑深部电刺激（DBS）是一种神经外科手术，用于治疗神经和 精神疾病最近对动物和人类的研究表明，DBS可能 治疗顽固性成瘾的有效方法我们以前建议使用DBS作为治疗 在大鼠动物模型中寻找药物的行为，并发现高频DBS（HF-DBS） 腹侧纹状体/腹侧核（VS/NAc）受损的消退吗啡诱导的 条件性位置偏爱（CPP），而低频DBS（LF-DBS）增强消退 记忆（减少药物寻求行为）。有趣的是，我们还发现LF-DBS 显著缩短了药物的持续时间（LF-DBS~10天vs假DBS ~40天）。在 在分子水平上，我们发现DBS治疗的动物增加了BDNF在脑组织中的表达， 海马区（HPC）。然而，在LF-DBS中，药物复吸并没有被显著阻止。 当仅在消退期期间施加刺激时，治疗动物。在这个过渡 在SCORE-SuRE赠款周期之间，我们建议进一步推进药物知识- 通过使用药理学方法，寻求行为以及DBS的潜在作用机制 和化学遗传学方法。因此，在本研究中，目标1a-c将确定 在消退期间应用LF-DBS，此外还在 药物复吸防止了更高比例的动物的药物寻求。关于BDNF 将在HPC以及其他脑区域中测量表达，即，杏仁核，VS/NAc， 和内侧前额叶皮质（mPFC）。目标2a将使用药理学方法， BDNF和TrkB拮抗剂（ANA-12）在VS/NAc中的作用，以确定它们在 吗啡CPP。由于HPC中的多巴胺能神经元包括神经元亚群， 为了表达BDNF，目标2b中的方法是使用化学遗传学工具，称为设计者， 受体专门激活的设计师药物（DREADDs），以激活HPC介导的 在ANA-12的存在下，神经元，以防止吗啡CPP的消退。激活 DREADD将使用氯氮平N-氧化物（CNO）进行。目标2c将取代HPC-NAc 神经元能/BDNF能投射，将阻止LF-DBS的有益作用。我们 研究代表了一种基于回路的方法，以更好地了解药物的作用机制， 寻找和灭绝。因为啮齿类动物的药物灭绝模型类似于 在人类的治疗中，有针对性的电刺激和DBS可能增加 前灭绝分子的表达可能代表了一种有效的未来方法，以减少 阿片类药物使用障碍（OUD）