Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal

早期戒断期间预防可卡因引起的前额叶 ERK 关闭

基本信息

项目摘要

DESCRIPTION (provided by applicant): This application will determine the mechanisms underlying a profound dephosphorylation of ERK MAP kinase and in the dorsomedial prefrontal cortex (PFC) during early withdrawal from cocaine self-administration (SA) that trigger persistent cocaine-seeking. We have demonstrated that ERK dephosphorylation (or "shutoff") in the PFC occurs within 2 hr of the end of repeated, daily cocaine SA. Reversing the ERK shutoff with a single infusion of brain-derived neurotrophic factor (BDNF) into the PFC normalizes glutamate transmission in the nucleus accumbens and suppresses cocaine-seeking in abstinent animals for as long as three weeks. However, BDNF is not a therapeutically useful medication because it is a neuropeptide that does not effectively cross the blood-brain barrier. Therefore, it is necessary to characterize the molecular mechanisms underlying the cocaine SA-induced ERK shutoff in order to identify alternative targets for medication development. We present a rationale and preliminary evidence to support the hypothesize that the ERK shutoff is mediated by GluN2B receptor activation of the ERK phosphatase, STEP. We propose to investigate this hypothesis in the following aims. In Aim 1, we will investigate changes in ERK phosphatase activation and the surface expression and synaptic/extrasynaptic distribution of NMDA receptors during early withdrawal from cocaine SA. In Aim 2, we will investigate whether antagonists of GluN2A or GluN2B receptors will suppress the cocaine-induced ERK/CREB shut-off in the PFC during early withdrawal and persistent cocaine-seeking after abstinence and extinction training. In Aim 3, we will investigate whether or not inhibition of calcineurin and the ERK phosphatases, STEP or protein phosphatase 2A, will reverse the cocaine-induced ERK/CREB shut-off during early withdrawal and suppress cocaine-seeking after abstinence and extinction training. These studies will impact the field of drug abuse research by advancing our understanding of the key neurobiological substrates that mediate cocaine-induced neuroadaptations and relapse to drug-seeking with the potential of leading to novel preventive interventions during early withdrawal.
描述(由申请人提供):本申请将确定在早期戒断可卡因自我给药(SA)期间触发持续性可卡因寻求的过程中,ERK MAP 激酶和背内侧前额叶皮层(PFC)发生深度去磷酸化的机制。我们已经证明,PFC 中的 ERK 去磷酸化(或“关闭”)会在每天重复使用可卡因 SA 结束后 2 小时内发生。通过向 PFC 中单次注入脑源性神经营养因子 (BDNF) 来逆转 ERK 关闭,可以使伏隔核中的谷氨酸传输正常化,并抑制戒断动物对可卡因的渴求长达三周。然而,BDNF 并不是一种有治疗作用的药物,因为它是一种不能有效穿过血脑屏障的神经肽。因此,有必要表征可卡因 SA 诱导的 ERK 关闭的分子机制,以确定药物开发的替代靶标。我们提出了基本原理和初步证据来支持 ERK 关闭是由 ERK 磷酸酶 STEP 的 GluN2B 受体激活介导的假设。我们建议按照以下目标研究这一假设。在目标 1 中,我们将研究早期戒除可卡因 SA 期间 ERK 磷酸酶激活以及 NMDA 受体的表面表达和突触/突触外分布的变化。在目标 2 中,我们将研究 GluN2A 或 GluN2B 受体拮抗剂是否会抑制可卡因诱导的 PFC 中 ERK/CREB ​​关闭,包括在戒断和灭绝训练后的早期戒断和持续可卡因寻求过程中。在目标 3 中,我们将研究抑制钙调神经磷酸酶和 ERK 磷酸酶、STEP 或蛋白磷酸酶 2A 是否会逆转早期戒断期间可卡因诱导的 ERK/CREB ​​关闭,并在戒断和灭绝训练后抑制可卡因寻求。这些研究将通过增进我们对介导可卡因诱导的神经适应和药物寻求复发的关键神经生物学底物的理解来影响药物滥用研究领域,并有可能在早期戒断期间产生新的预防干预措施。

项目成果

期刊论文数量(0)
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Jacqueline F. McGinty其他文献

Oxytocin decreases methamphetamine-seeking and gene expression changes in rats after traumatic stress
  • DOI:
    10.1016/j.drugalcdep.2016.08.382
  • 发表时间:
    2017-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jacqueline F. McGinty
  • 通讯作者:
    Jacqueline F. McGinty
Seizure-Induced Alterations of Opioid Peptide and Zinc Metabolism in the Hippocampus of Rats
癫痫发作引起的大鼠海马阿片肽和锌代谢的改变
  • DOI:
    10.1016/b978-0-12-506455-2.50027-7
  • 发表时间:
    1988
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Jacqueline F. McGinty;Tomoyuki Kanamatsu;Jau;JOHN D. Morton;Christopher J. Frederickson
  • 通讯作者:
    Christopher J. Frederickson
Will the promise of translational neuropsychopharmacology research ever deliver? The lion’s roar; the kitten’s purr
转化神经精神药理学研究的前景能否实现?
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jacqueline F. McGinty;Victoria Arango;Kathleen T. Brady;Sandra D. Comer;Rita Z. Goldstein;E. Nestler;William W. Stoops;Michael A. Nader
  • 通讯作者:
    Michael A. Nader
Erratum to: Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex
  • DOI:
    10.1007/s00213-013-3155-0
  • 发表时间:
    2013-06-05
  • 期刊:
  • 影响因子:
    3.300
  • 作者:
    Wei-Lun Sun;Agnieszka Zelek-Molik;Jacqueline F. McGinty
  • 通讯作者:
    Jacqueline F. McGinty
Lennart Heimer: in memoriam (1930–2007)
  • DOI:
    10.1007/s00429-008-0194-0
  • 发表时间:
    2008-08-08
  • 期刊:
  • 影响因子:
    2.900
  • 作者:
    Suzanne N. Haber;Jacqueline F. McGinty;Enrico Mugnaini;Laszlo Zaborszky
  • 通讯作者:
    Laszlo Zaborszky

Jacqueline F. McGinty的其他文献

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{{ truncateString('Jacqueline F. McGinty', 18)}}的其他基金

Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
  • 批准号:
    10674953
  • 财政年份:
    2020
  • 资助金额:
    $ 31.26万
  • 项目类别:
Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
  • 批准号:
    10268963
  • 财政年份:
    2020
  • 资助金额:
    $ 31.26万
  • 项目类别:
Pathway-specific Intervention in Prelimbic Cortical Circuitry Decreases Cocaine-seeking
对前额皮质回路进行特定通路干预可减少可卡因寻求
  • 批准号:
    10453594
  • 财政年份:
    2020
  • 资助金额:
    $ 31.26万
  • 项目类别:
COCA: Pilot Core C
COCA:试点核心 C
  • 批准号:
    10404583
  • 财政年份:
    2019
  • 资助金额:
    $ 31.26万
  • 项目类别:
COCA: Pilot Core C
COCA:试点核心 C
  • 批准号:
    10630227
  • 财政年份:
    2019
  • 资助金额:
    $ 31.26万
  • 项目类别:
COCA - Project 2 Preventing Drug-induced Neuroadaptations in Prelimbic Cortex
COCA - 项目 2 预防前边缘皮层药物诱导的神经适应
  • 批准号:
    10630231
  • 财政年份:
    2019
  • 资助金额:
    $ 31.26万
  • 项目类别:
COCA - Project 2 Preventing Drug-induced Neuroadaptations in Prelimbic Cortex
COCA - 项目 2 预防前边缘皮层药物诱导的神经适应
  • 批准号:
    10404585
  • 财政年份:
    2019
  • 资助金额:
    $ 31.26万
  • 项目类别:
WCBR Conference Grant
WCBR 会议补助金
  • 批准号:
    9045099
  • 财政年份:
    2016
  • 资助金额:
    $ 31.26万
  • 项目类别:
Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal
早期戒断期间预防可卡因引起的前额叶 ERK 关闭
  • 批准号:
    8787464
  • 财政年份:
    2013
  • 资助金额:
    $ 31.26万
  • 项目类别:
Prevention of Cocaine-induced Prefrontal ERK Shutoff During Early Withdrawal
早期戒断期间预防可卡因引起的前额叶 ERK 关闭
  • 批准号:
    8439031
  • 财政年份:
    2013
  • 资助金额:
    $ 31.26万
  • 项目类别:

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