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

项目摘要

DESCRIPTION (provided by applicant): 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 electro physiologically determine if the unregulated GluN2B receptors I found in nicotine-extinguished animals are extra synaptic and necessary for cued nicotine seeking. I will accomplish this with an innovative set of techniques including a coagonist degradation procedure using whole cell patch clamp, and administration of siRNA constructs to down regulate 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 extra synaptic 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.
描述(由申请人提供):尼古丁滥用和成瘾对健康造成很大的负担。事实上,据估计,全球每年有600万人死于与吸烟有关的疾病,但目前有20%的成年人吸烟,而在试图戒烟的人中,90%的人复发。尼古丁是烟草中的主要活性生物碱,由动物自行给药,并在与药物奖励相关的大脑区域产生细胞适应,如伏隔核。由于吸烟行为对线索的依赖,接触尼古丁相关线索是复发的危险因素。在这里,我研究了神经胶质谷氨酸运输的作用 而NMDA受体与尼古丁复发易感性有关。我发现伏隔核的核心谷氨酸能机制与尼古丁复发有关,包括突触强度增加(测量为脊髓直径和AMPA电流的增加)和伴随的蛋白质变化(包括胶质细胞谷氨酸转运体GLT1的减少,以及AMPA亚单位GluA1和NMDA亚单位GluN2B的增加)。在拟议的获奖期内,我将探索调节线索尼古丁恢复的机制,以及复发易感性潜在的神经元-神经胶质细胞相互作用。在K99的目标中,我建议从功能上描述尼古丁介导的GLT1下调,并确定它在恢复尼古丁寻求中的作用。要做到这一点,我将学习谷氨酸摄取和全细胞膜片钳电生理学策略,以及应用我在F32 NRSA期间获得的蛋白质印迹和脑内微注射技能。我还将使用反义活体吗啡和头孢曲松来研究上调或下调GLT1对恢复尼古丁寻求的影响。我将在R00期间使用这些技术来进一步表征GluN2B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R00期间,我将从电生理学上确定我在尼古丁灭活的动物身上发现的未受调控的GluN2B受体是否是额外的突触,对于线索尼古丁的寻找是必要的。我将通过一套创新的技术来实现这一点,包括使用全细胞膜片钳的共激剂降解过程,以及给药siRNA构建体以下调尼古丁熄灭动物中的GluN2B,以确定使该蛋白正常化是否抑制尼古丁熄灭动物中暗示的尼古丁寻找。这将是 提示谷氨酸溢出和额外突触NMDA受体的激活在复发易感性中起关键作用。接下来,我将确定用siRNA恢复GluN2B或用头孢曲松恢复GLT1是否分别间接恢复GLT1或GluN2B,这表明在线索诱导的尼古丁复发中存在神经元-胶质细胞相互作用。最后,我将研究恢复GluN2B或GLT1是否会阻止我之前在提示尼古丁恢复期间发现的快速、瞬时突触可塑性。这些实验有可能揭示尼古丁成瘾的新的神经生物学机制,并可能有助于开发旨在逆转尼古丁诱导的神经生物学改变的新的治疗方案。

项目成果

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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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    9978489
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    $ 24.9万
  • 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:
    10899797
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:

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