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
基本信息
- 批准号:10629686
- 负责人:
- 金额:$ 14.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Amygdaloid structureAnimal ModelAnimalsAreaAttenuatedBehavioralBiologicalBrainBrain DiseasesBrain regionBrain-Derived Neurotrophic FactorCOVID-19 pandemicCessation of lifeCholera ToxinClinicClozapineCuesDataDeep Brain StimulationDorsalDrug ModelingsElectric StimulationExtinctionFrequenciesFutureGeneticGenetic TechniquesGlutamatesGrantHippocampusHumanImpairmentImplanted ElectrodesInjectionsKnowledgeLocationMeasuresMedialMemoryMental disordersMolecularMorphineMovement DisordersNeuronsNeurosurgical ProceduresNeurotrophic Tyrosine Kinase Receptor Type 2Nucleus AccumbensOpiate AddictionOpioidOverdoseOxidesPersonsPharmaceutical PreparationsPharmacological TreatmentPhasePhysiologic pulsePilot ProjectsPopulationPrefrontal CortexPrincipal InvestigatorProceduresProcessRattusRefractoryRelapseReportingResearchResearch PersonnelResearch Project GrantsResistanceRewardsRodentRodent ModelRoleSubstance Use DisorderTimeVentral Striatumaddictionantagonistcocaine overdoseconditioned place preferencecost estimatedesigner receptors exclusively activated by designer drugsdrug seeking behaviordrug testingexperimental studygenetic approachgenetic manipulationimmunoreactivityinsightlearning extinctionnervous system disorderopioid use disorderpharmacologicpreventprogramsreduce symptomsretrograde transportsobrietysuicidal morbiditytool
项目摘要
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)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jennifer Luz Barreto Estrada其他文献
Jennifer Luz Barreto Estrada的其他文献
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{{ truncateString('Jennifer Luz Barreto Estrada', 18)}}的其他基金
G-RISE at the University of Puerto Rico Medical Sciences Campus
波多黎各大学医学科学校区的 G-RISE
- 批准号:
10558147 - 财政年份:2023
- 资助金额:
$ 14.9万 - 项目类别:
EFFECT OF ANDROGENS ON BEHAVIOR THROUGH NPY MODULATION
雄激素通过 NPY 调节对行为的影响
- 批准号:
8360152 - 财政年份:2011
- 资助金额:
$ 14.9万 - 项目类别:
CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH REPRODUCTIVE HEALTH
与生殖健康相关的细胞和分子变化
- 批准号:
8167857 - 财政年份:2010
- 资助金额:
$ 14.9万 - 项目类别:
CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH REPRODUCTIVE HEALTH
与生殖健康相关的细胞和分子变化
- 批准号:
7960056 - 财政年份:2009
- 资助金额:
$ 14.9万 - 项目类别:
CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH REPRODUCTIVE HEALTH
与生殖健康相关的细胞和分子变化
- 批准号:
7720870 - 财政年份:2008
- 资助金额:
$ 14.9万 - 项目类别:
CELLULAR AND MOLECULAR CHANGES ASSOCIATED WITH REPRODUCTIVE HEALTH
与生殖健康相关的细胞和分子变化
- 批准号:
7610164 - 财政年份:2007
- 资助金额:
$ 14.9万 - 项目类别:
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