Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration

中脑 GABA 电路的改变可促进可卡因的自我管理

基本信息

  • 批准号:
    10574548
  • 负责人:
  • 金额:
    $ 53.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-05-15 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Project Summary. Cocaine is the most widely abused psychostimulant by a wide margin, and it remains a major public health problem in the US. Cocaine use was slowly declining, but in recent years there has been a resurgence in cocaine abuse accompanied by a sharp increase in cocaine-related hospitalizations and deaths. These facts highlight the need for effective medications for cocaine use disorder (CUD) because there are presently no FDA- approved pharmacologic treatments for CUD. Our exciting preliminary results highlight a novel molecular substrate that could be targeted to attenuate or prevent cocaine taking and seeking. Specifically, we show that cocaine exposure alters the expression of KCC2, a K+-Cl- cotransporter that defines the Cl- gradient in midbrain GABA neurons. Importantly, this cocaine-induced neuroadaptation is associated with circuitry changes in midbrain GABA neurons that promote and elevate further cocaine taking. These findings support the working hypothesis that initial cocaine taking alters midbrain GABAergic circuitry and increases the vulnerability for increased cocaine consumption over time. Thus, KCC2 represents a potential therapeutic target to treat CUD. KCC2 is expressed primarily in the central nervous system, and it is amenable to therapeutic manipulation in humans. KCC2 is highly attractive as a therapeutic target because it is usually constitutively highly active. Therefore, when normal subjects are treated with KCC2 activators, KCC2 activity is already high, such that attempts to increase its activity further do not produce deleterious side effects. Under normal physiological conditions, KCC2 maintains a low intra-neuronal Cl- concentration required for hyperpolarizing, inhibitory GABAergic currents. Our preliminary results indicate that cocaine dose-dependently downregulates KCC2 function in midbrain GABA neurons, thereby altering midbrain GABAergic circuitry. As a consequence of these circuitry changes, downregulation of KCC2 leads to increased cocaine self-administration. That is, cocaine use itself, by downregulating KCC2, perpetuates heavy cocaine self-administration. Our preliminary results indicate that if we prevent KCC2 downregulation or correct KCC2 function, then we decrease cocaine self-administration. The overall goal of this proposal is to characterize the functional state of the midbrain GABAergic circuitry and the disposition of KCC2 function during cocaine self-administration, extinction, and the reinstatement of cocaine seeking (Aims1 & 2). At each phase of the addiction cycle, we will determine the functional state of the midbrain GABAergic circuitry as a causal contributor to cocaine taking or seeking. Finally, we will apply two mechanistically different pharmacotherapies to boost KCC2 function to decrease cocaine self-administration and cocaine-seeking behavior during abstinence (Aim3). These translationally-relevant studies will test potential therapeutic drugs acting to boost KCC2 function to mitigate enhanced cocaine self-administration induced by cocaine itself. The proposed studies of KCC2 as a novel therapeutic target to mitigate CUD are timely, highly significant, and appropriately aimed at the factors underlying the transition to heavy cocaine use.
项目摘要。 可卡因是滥用最广泛的精神兴奋剂,并且仍然是主要的公众药物 美国的健康问题。可卡因的使用缓慢下降,但近年来有所回升 可卡因滥用伴随着与可卡因相关的住院和死亡人数急剧增加。这些事实 强调需要针对可卡因使用障碍 (CUD) 的有效药物,因为目前 FDA 还没有 批准的 CUD 药物治疗。我们令人兴奋的初步结果突出了一种新型分子 可用于减少或防止可卡因吸食和寻找的底物。具体来说,我们表明 可卡因暴露会改变 KCC2 的表达,KCC2 是一种 K+-Cl- 协同转运蛋白,定义中脑中的 Cl- 梯度 GABA 神经元。重要的是,这种可卡因诱导的神经适应与神经回路的变化有关 中脑 GABA 神经元促进和提高进一步可卡因的摄入。这些发现支持了工作 假设最初服用可卡因会改变中脑 GABA 电路并增加对可卡因的脆弱性 随着时间的推移,可卡因的消费量增加。因此,KCC2 代表了治疗 CUD 的潜在治疗靶点。 KCC2 主要在中枢神经系统中表达,并且适合治疗操作 在人类中。 KCC2 作为治疗靶点非常有吸引力,因为它通常具有高度活性。 因此,当正常受试者接受KCC2激活剂治疗时,KCC2活性已经很高,使得 进一步增加其活性的尝试不会产生有害的副作用。正常生理情况下 条件下,KCC2 维持超极化、抑制所需的低神经元内 Cl- 浓度 GABA能电流。我们的初步结果表明,可卡因剂量依赖性地下调 KCC2 功能 中脑 GABA 神经元,从而改变中脑 GABA 能电路。由于这些电路 变化时,KCC2 的下调会导致可卡因自我给药增加。也就是说,可卡因通过自身使用 下调 KCC2,使重度可卡因自我给药永久化。我们的初步结果表明,如果我们 防止 KCC2 下调或纠正 KCC2 功能,然后我们减少可卡因自我给药。 该提案的总体目标是表征中脑 GABAergic 电路的功能状态 以及可卡因自我给药、灭绝和恢复过程中 KCC2 功能的处置 寻找可卡因(目标 1 和 2)。在成瘾周期的每个阶段,我们将确定成瘾周期的功能状态 中脑 GABA 能回路是吸食或寻找可卡因的因果因素。最后,我们将应用两个 机制上不同的药物疗法可增强 KCC2 功能,减少可卡因自我给药和 戒断期间寻求可卡因的行为(目标 3)。这些与转化相关的研究将测试潜力 治疗药物可增强 KCC2 功能,以减轻由可卡因引起的增强的可卡因自我给药 可卡因本身。 KCC2 作为减轻 CUD 的新治疗靶点的拟议研究是及时的、高度的 重要的,并适当针对向可卡因大量使用过渡的潜在因素。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

John A. Dani其他文献

Addictive Behaviors Differential cigarette-related startle cue reactivity among light , moderate , and heavy smokers
成瘾行为 轻度、中度和重度吸烟者与香烟相关的惊吓提示反应的差异
  • DOI:
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yong Cui;Jason D. Robinson;F. Versace;Cho Y. Lam;Jennifer A. Minnix;M. Karam;John A. Dani;T. Kosten;D. Wetter;Victoria L. Brown;P. Cinciripini
  • 通讯作者:
    P. Cinciripini
Structure, diversity, and ionic permeability of neuronal and muscle acetylcholine receptors.
神经元和肌肉乙酰胆碱受体的结构、多样性和离子渗透性。
  • DOI:
  • 发表时间:
    1993
  • 期刊:
  • 影响因子:
    0
  • 作者:
    John A. Dani
  • 通讯作者:
    John A. Dani
Nicotine activates a dopamine signal that enables <em>in vivo</em> synaptic plasticity of the kind that underlies associative memory
  • DOI:
    10.1016/j.bcp.2009.06.054
  • 发表时间:
    2009-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jianrong Tang;John A. Dani
  • 通讯作者:
    John A. Dani
Acetylcholine-Activated Channel Current-Voltage Relations in Symmetrical Na<sup>+</sup> Solutions
  • DOI:
    10.1016/s0006-3495(84)84087-4
  • 发表时间:
    1984-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    John A. Dani;George Eisenman
  • 通讯作者:
    George Eisenman

John A. Dani的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('John A. Dani', 18)}}的其他基金

Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration
中脑 GABA 电路的改变可促进可卡因的自我管理
  • 批准号:
    10183525
  • 财政年份:
    2021
  • 资助金额:
    $ 53.56万
  • 项目类别:
Altered Midbrain GABAergic Circuitry Drives Greater Cocaine Self-administration
中脑 GABA 电路的改变可促进可卡因的自我管理
  • 批准号:
    10405526
  • 财政年份:
    2021
  • 资助金额:
    $ 53.56万
  • 项目类别:
Adolescent Exposure to Stress or Nicotine Increases Rodent Alcohol Self-Administration
青少年接触压力或尼古丁会增加啮齿动物的自我饮酒
  • 批准号:
    10453734
  • 财政年份:
    2019
  • 资助金额:
    $ 53.56万
  • 项目类别:
Adolescent Exposure to Stress or Nicotine Increases Rodent Alcohol Self-Administration
青少年接触压力或尼古丁会增加啮齿动物的自我饮酒
  • 批准号:
    10224039
  • 财政年份:
    2019
  • 资助金额:
    $ 53.56万
  • 项目类别:
Adolescent Exposure to Stress or Nicotine Increases Rodent Alcohol Self-Administration
青少年接触压力或尼古丁会增加啮齿动物的自我饮酒
  • 批准号:
    10671050
  • 财政年份:
    2019
  • 资助金额:
    $ 53.56万
  • 项目类别:
Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction
Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素
  • 批准号:
    8609960
  • 财政年份:
    2014
  • 资助金额:
    $ 53.56万
  • 项目类别:
Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction
Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素
  • 批准号:
    9054103
  • 财政年份:
    2014
  • 资助金额:
    $ 53.56万
  • 项目类别:
Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction
Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素
  • 批准号:
    9428198
  • 财政年份:
    2014
  • 资助金额:
    $ 53.56万
  • 项目类别:
Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction
Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素
  • 批准号:
    9482807
  • 财政年份:
    2014
  • 资助金额:
    $ 53.56万
  • 项目类别:
Alpha 5 nAChR is a Risk Factor within the Dopamine System for Nicotine Addiction
Alpha 5 nAChR 是多巴胺系统内尼古丁成瘾的危险因素
  • 批准号:
    9686812
  • 财政年份:
    2014
  • 资助金额:
    $ 53.56万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 53.56万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了