The role of dopamine in modulating relapse-induced transient synaptic plasticity

多巴胺在调节复发引起的瞬时突触可塑性中的作用

基本信息

  • 批准号:
    9926487
  • 负责人:
  • 金额:
    $ 0.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-01 至 2021-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Cocaine produces enduring alterations in nucleus accumbens core (NAcore) synaptic plasticity associated with relapse vulnerability. Specifically, cocaine self-administration causes enduring increases in dendritic spine head diameter, AMPA/NMDA ratios, and matrix metalloproteinase (MMP) activity. Re-exposure to cocaine- conditioned cues after extinction produces further rapid, transient synaptic potentiation (t-SP) within 15 min that is quantified with any of these measurements. However, when inducing reinstatement with a noncontingent cocaine injection the time course of t-SP differs in that the maximal response is not observed until 45 min. This discrepancy led to the hypothesis that while cues immediately drive forward drug seeking and t-SP, when reinstatement is initiated by noncontingent cocaine, the drug initially suppresses drug seeking and t-SP until pharmacological effects diminish below a threshold. A reinstatement model to evaluate this interaction between cue-induced cocaine seeking leading to cocaine use modeling many important features of human relapse was developed. Preliminary data show that contingent cocaine reverses cue-induced t-SP and discontinuation of this access rapidly restores t-SP. Cocaine increases synaptic dopamine (DA) as a competitive inhibitor of the dopamine transporter, thus dopaminergic mechanisms were hypothesized to contribute to cocaine's effects on cue-induced t-SP. Here, the role of cocaine-induced ventral tegmental area (VTA) DA transmission in t-SP reversal is examined using viral-based designer receptors exclusively activated by designer drugs (DREADD) and tyrosine hydroxylase-Cre (TH-Cre) transgenic rats to introduce anatomical and cell-type specificity. To accomplish this, the candidate will learn in vivo zymography to analyze MMP activity and patch clamp electrophysiology (Aim 1), as well as employ dendritic spine analysis and intracranial microinjection skills acquired during F32 NRSA training. In the K99 aims, the contribution of VTA DA in cocaine-induced reversal of NAcore t-SP will be characterized. Preliminary data show that cocaine-trained rats with Gq-DREADD in VTA TH+ cells will reinstate to a CNO priming injection and it will be further assessed whether this activation likewise blunts cue-induced t-SP. The impact of selective activation (Aim 2B) or inactivation of VTA DA cell bodies (Aim 2A) or terminal field regions (Aim 2C) on cue-induced t-SP and cocaine-induced suppression of t- SP will be examined. During the R00 period, chronic Gq-DREADD activation with CNO self-administration will be used to test the sufficiency for VTA DA activity to reproduce potentiated neuroplasticity produced by chronic cocaine (Aim 3). Furthermore, the dynamic regulation of glutamate and DA release in the reinstatement model will be assessed with microdialysis (Aim 4). These experiments have the potential to contribute to the development of novel therapeutic options aimed at reversing cocaine-induced neurobiological alterations.


项目成果

期刊论文数量(0)
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SADE MONIQUE SPENCER其他文献

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{{ truncateString('SADE MONIQUE SPENCER', 18)}}的其他基金

Glutamatergic plasticity that drives cannabinoid withdrawal and craving
谷氨酸可塑性导致大麻素戒断和渴望
  • 批准号:
    10743526
  • 财政年份:
    2023
  • 资助金额:
    $ 0.82万
  • 项目类别:
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
  • 批准号:
    10593045
  • 财政年份:
    2022
  • 资助金额:
    $ 0.82万
  • 项目类别:
Targeting adenosine monophosphate activated protein kinase (AMPK) to reduce cocaine relapse
靶向单磷酸腺苷激活蛋白激酶 (AMPK) 减少可卡因复吸
  • 批准号:
    10303255
  • 财政年份:
    2022
  • 资助金额:
    $ 0.82万
  • 项目类别:
The role of dopamine in modulating relapse-induced transient synaptic plasticity
多巴胺在调节复发引起的瞬时突触可塑性中的作用
  • 批准号:
    9751826
  • 财政年份:
    2018
  • 资助金额:
    $ 0.82万
  • 项目类别:
Role of Alpha2delta-1 in Cocaine Relapse and Gabapentin Mechanisms of Action
Alpha2delta-1 在可卡因复发中的作用和加巴喷丁的作用机制
  • 批准号:
    8839664
  • 财政年份:
    2014
  • 资助金额:
    $ 0.82万
  • 项目类别:
Role of Alpha2delta-1 in Cocaine Relapse and Gabapentin Mechanisms of Action
Alpha2delta-1 在可卡因复发中的作用和加巴喷丁的作用机制
  • 批准号:
    8716830
  • 财政年份:
    2014
  • 资助金额:
    $ 0.82万
  • 项目类别:
The role of dopaminergic transmission in the development of manic-like behaviors
多巴胺能传递在躁狂样行为发展中的作用
  • 批准号:
    8111205
  • 财政年份:
    2010
  • 资助金额:
    $ 0.82万
  • 项目类别:
The role of dopaminergic transmission in the development of manic-like behaviors
多巴胺能传递在躁狂样行为发展中的作用
  • 批准号:
    7913994
  • 财政年份:
    2010
  • 资助金额:
    $ 0.82万
  • 项目类别:
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