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/摘要
脑深部刺激(DBS)是一种神经外科手术,用于治疗神经病学和
精神障碍。最近对动物和人类的研究表明,DBS可能是
一种治疗难治性成瘾的有效方法。我们之前建议使用星展银行作为治疗手段
在大鼠动物模型上寻找药物行为,并发现高频DBS(HF-DBS)
腹侧纹状体/伏隔核(VS/NAC)对吗啡诱导的消退的影响
条件性位置偏爱(CPP),而低频DBS(LF-DBS)增强消退
记忆(减少寻药行为)。有趣的是,我们还发现LF-DBS
显著缩短药物持续期(LF-DBS~10d与Sham-DBS~40d)。在…
在分子水平上,我们发现DBS处理的动物增加了脑源性神经营养因子的表达。
海马(HPC)。然而,在LF-DBS-DBS中,药物恢复没有明显的预防作用。
仅在绝育过程中进行刺激时才对动物进行处理。在这一转型中
在成绩确定的资助周期之间,我们建议进一步提高药物方面的知识-
寻求行为,以及在潜在的DBS的作用机制中,通过使用药理学
和化学发生的方法。因此,在本研究中,目标1a-c将决定是否
在消亡期间应用LF-DBS,除了在脑电刺激阶段
药物恢复可防止在更高比例的动物中寻求药物。此外,BDNF
将测量HPC以及其他大脑区域,即杏仁核、VS/NAC、
内侧前额叶皮质(MPFC)。Aim 2a将使用一种药理学方法通过注入
脑源性神经营养因子和TrkB拮抗剂(ANA-12)在VS/NAC消退中的作用
吗啡CPP。由于HPC中的谷氨酸能神经元包含一个神经元亚群
表达BDNF,目标2b中的方法是使用化学发生工具,称为Designer
由特制药物(DREADD)特异性激活的受体可激活HPC谷氨酸能
神经元中存在ANA-12,防止吗啡CPP消退。激活
DREADDS将与氯氮平N-氧化物(CNO)一起完成。AIM 2c将停用HPC-NAC
谷氨酸/BDN能投射将阻止LF-DBS的有益影响。我们的
这项研究代表了一种基于电路的方法,以更好地了解药物的作用机制
寻找和灭绝。因为药物灭绝的啮齿动物模型类似于基于暴露的
在人类的治疗中,有可能靶向电刺激和DBS-增加
表达促进消亡的分子可能代表着未来减少
成瘾症状和阿片类药物使用障碍(OUD)。
项目成果
期刊论文数量(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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