Contributions of Glial Glutamate Transport and NMDA Receptors in Nicotine Relapse
胶质细胞谷氨酸转运和 NMDA 受体在尼古丁复吸中的作用
基本信息
- 批准号:8618455
- 负责人:
- 金额:$ 13.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-05-15 至 2016-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAlkaloidsAnimalsAwardBiological AssayBrainBrain regionCaliberCeftriaxoneCellsCessation of lifeChemosensitizationCuesDataDendritic SpinesDependencyDevelopmentDiseaseDown-RegulationDrug AddictionElectrophysiology (science)Exposure toGlutamate TransporterGlutamatesHeadHealthIntravenousLearningMeasuresMediatingMentorsMethodsMicroinjectionsMorphologyN-Methyl-D-Aspartate ReceptorsN-MethylaspartateNational Research Service AwardsNeurobiologyNeurogliaNeuronsNicotineNicotine DependenceNucleus AccumbensOutcomePharmaceutical PreparationsPharmacotherapyPhaseProceduresPropertyProteinsRattusRelapseResearchRisk FactorsRoleSalineSelf AdministrationSelf-AdministeredSliceSmall Interfering RNASmokeSmokingSmoking BehaviorSynapsesSynaptic plasticityTechniquesTissuesTobaccoTobacco DependenceTobacco smokingTrainingTreatment EfficacyUp-RegulationVertebral columnWestern Blottingcigarette smokingdesigndrug abstinencedrug developmentdrug rewardinnovationknock-downneurobiological mechanismneurochemistryneuropsychiatrynicotine abusenovelnovel therapeuticspatch clamppreventprogramsprotein functionpublic health relevancereceptorreduce tobacco useresearch studyskillsuptake
项目摘要
Project Summary/Abstract
Nicotine abuse and addiction represents a large health liability. Indeed, cigarette smoking-related illness
results in an estimated 6,000,000 deaths per year worldwide, yet 20% of adults currently smoke, and among
those who attempt to quit, >90% relapse. Nicotine, the primary active alkaloid in tobacco, is self-administered
by animals and produces cellular adaptations in brain regions associated with drug reward, such as the
nucleus accumbens. Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is
a risk factor for relapse. Here, I examine the role of glial glutamate transport and NMDA receptors in nicotine
relapse vulnerability. I have found that nucleus accumbens core glutamatergic mechanisms are involved in
nicotine relapse, including increased synaptic strength (measured as increased spine diameter and AMPA
currents) and accompanying protein changes (including a decrease in the glial glutamate transporter, GLT1,
and increases in the AMPA subunit GluA1 and NMDA subunit GluN2B). During the proposed award period, I
will explore the mechanisms mediating cued nicotine reinstatement and a possible neuron-glia interaction
underlying relapse vulnerability. In the K99 aims, I propose to functionally characterize nicotine-mediated
down-regulation of GLT1, and to determine its role in reinstated nicotine seeking. To do this, I will learn
glutamate uptake and whole cell patch clamp electrophysiology strategies, as well as employ my Western blot
and intracranial microinjection skills I acquired during my F32 NRSA. I will also use antisense vivo
morpholinos and ceftriaxone to examine the impact of up- or down-regulated GLT1 on reinstatement of
nicotine seeking. I will employ these techniques during the R00 period to further characterize the role of
GluN2B in cue-reinstated nicotine seeking, and to explore a potential neuron-glia interaction mediating nicotine
relapse. During the R00 period, I will electrophysiologically determine if the upregulated GluN2B receptors I
found in nicotine-extinguished animals are extrasynaptic and necessary for cued nicotine seeking. I will
accomplish this with an innovative set of techniques including a coagonist degredation procedure using whole
cell patch clamp, and administration of siRNA constructs to downregulate GluN2B in nicotine-extinguished
animals to determine if normalizing this protein inhibits cued nicotine seeking in nicotine-extinguished animals.
This will indicate a key role of glutamate overflow and activation of extrasynaptic NMDA receptors in relapse
vulnerability. Next, I will determine if restoring GluN2B with siRNA or GLT1 with ceftriaxone indirectly restores
GLT1 or GluN2B, respectively, indicating a neuron-glia interaction in cue-induced nicotine relapse. Finally, I will
examine if restoring GluN2B or GLT1 prevents the rapid, transient synaptic plasticity I previously found during
cued nicotine reinstatement. These experiments have the potential to reveal novel neurobiological
mechanisms of nicotine addiction, and could contribute to the development of novel therapeutic options aimed
at reversing nicotine-induced neurobiological alterations.
项目总结/摘要
尼古丁滥用和成瘾是一个很大的健康负担。事实上,吸烟相关疾病
据估计,全球每年有600万人死于吸烟,但目前有20%的成年人吸烟,
那些试图戒烟的人,>90%复发。尼古丁是烟草中主要的活性生物碱,
并在与药物奖励相关的大脑区域产生细胞适应,例如
丘脑核由于吸烟行为的线索依赖性,暴露于尼古丁相关的线索,
复发的危险因素在这里,我研究神经胶质谷氨酸转运和NMDA受体在尼古丁中的作用。
易复发我已经发现,丘脑核的核心多巴胺能机制参与了
尼古丁复发,包括突触强度增加(测量为棘直径增加和AMPA增加)
电流)和伴随的蛋白质变化(包括神经胶质谷氨酸转运蛋白,GLT 1,
AMPA亚基GluA 1和NMDA亚基GluN 2B增加)。在建议的授标期间,我
将探讨介导线索尼古丁恢复的机制和可能的神经元-胶质细胞相互作用
潜在的复发脆弱性在K99的目标中,我建议在功能上表征尼古丁介导的
下调GLT 1,并确定其在恢复尼古丁寻求中的作用。为了做到这一点,我将学习
谷氨酸摄取和全细胞膜片钳电生理学策略,以及采用我的蛋白质印迹
以及我在F32 NRSA手术中学到的颅内显微注射技术我也会用反义活体
研究GLT 1上调或下调对恢复
寻找尼古丁我将在R 00期间使用这些技术来进一步描述
GluN 2B在线索恢复的尼古丁寻找中的作用,并探索潜在的神经元-胶质细胞相互作用介导尼古丁
复发在R 00期间,我将通过电生理学方法确定上调的GluN 2B受体I
在尼古丁熄灭的动物中发现的突触外神经元是寻找尼古丁线索所必需的。我会
通过一套创新的技术来实现这一点,包括使用整个
细胞膜片钳和施用siRNA构建体以下调尼古丁熄灭的细胞中的GluN 2B。
动物,以确定正常化这种蛋白质是否抑制尼古丁熄灭动物的线索尼古丁寻求。
这将表明谷氨酸溢出和突触外NMDA受体激活在复发中的关键作用
易损性.接下来,我将确定用siRNA恢复GluN 2B或用头孢曲松恢复GLT 1是否间接恢复了GluN 2B。
GLT 1或GluN 2B,分别表明神经元-神经胶质细胞的相互作用的线索诱导尼古丁复吸。最后要
检查恢复GluN 2B或GLT 1是否会阻止我之前在研究中发现的快速,短暂的突触可塑性。
提示尼古丁恢复这些实验有可能揭示新的神经生物学
尼古丁成瘾的机制,并可能有助于开发新的治疗方案,
逆转尼古丁引起的神经生物学改变。
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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Cassandra D Gipson-Reichardt其他文献
Cassandra D Gipson-Reichardt的其他文献
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{{ truncateString('Cassandra D Gipson-Reichardt', 18)}}的其他基金
Neurobehavioral mechanisms underlying xylazine and fentanyl co-use and withdrawal
赛拉嗪和芬太尼共同使用和戒断的神经行为机制
- 批准号:
10737712 - 财政年份:2023
- 资助金额:
$ 13.11万 - 项目类别:
Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献
- 批准号:
10710219 - 财政年份:2022
- 资助金额:
$ 13.11万 - 项目类别:
Contributions of Progestins Independently and Interactively with Contraceptive Estrogen to Nicotine Use
孕激素独立和与避孕雌激素相互作用对尼古丁使用的贡献
- 批准号:
10592661 - 财政年份:2022
- 资助金额:
$ 13.11万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10214266 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10669480 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10231269 - 财政年份:2020
- 资助金额:
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Glutamergic Mechanisms in Opioid and Cocaine Co-Use
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- 批准号:
9978489 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684702 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
Glutamergic Mechanisms in Opioid and Cocaine Co-Use
阿片类药物和可卡因共同使用的谷氨酸机制
- 批准号:
10264811 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
Neuroinflammatory and glutamatergic mechanisms of nicotine seeking
寻求尼古丁的神经炎症和谷氨酸机制
- 批准号:
10684352 - 财政年份:2020
- 资助金额:
$ 13.11万 - 项目类别:
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