Prefrontal mechanisms underlying polydrug heroin and alcohol use

多种药物海洛因和酒精使用的前额叶机制

基本信息

  • 批准号:
    10739702
  • 负责人:
  • 金额:
    $ 49.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-15 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Opioid use disorder (OUD) is often comorbid with other drug use, and alcohol is one of the most commonly co- used drugs. Yet most of the basic research on OUD has been conducted in single-drug use models. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). These treatments establish the mu opioid receptor (MOR) as a major therapeutic target for OUD. Similarly, opioids have been implicated in the pathophysiology of alcohol use disorder (AUD), and naltrexone is used to treat both OUD and AUD, further underscoring the overlapping mechanisms between these disorders. As the seat of executive function, the prefrontal cortex plays an integral role in the inhibitory control over drug craving and relapse. Humans with substance use disorders (SUDs) exhibit structural and functional changes in the prefrontal cortex, accompanied by deficits in cognitive function. Thus, the prefrontal cortex may be a key locus for opioid-induced adaptations that impact SUD severity. My lab has identified the rodent infralimbic (IL) prefrontal cortex projection to the nucleus accumbens shell (ILNAshell) as an important limiter of heroin seeking. Within the IL cortex, interneurons express MORs, and layer 5 pyramidal neurons (which give rise to the NAshell projection) express 5-HT2A receptors. Furthermore, we have recently demonstrated the ability of a 5-HT2A agonist to reduce opioid and alcohol seeking (in single-drug use models), and these effects were long-lasting after a single treatment. Thus, 5-HT2A agonists are an emerging class of therapeutics for OUD and AUD, and they may act upon prefrontal cortex microcircuits to elicit these effects. This proposal aims to examine these two receptor systems, with a focus on the prefrontal cortex, in a preclinical model of polydrug heroin and alcohol use. This model incorporates chronic comorbid alcohol exposure, initiated prior to heroin self-administration and continuing throughout the period of opioid exposure. The overarching objectives of this project are to identify the role of 5- HT2A receptors in drug seeking after comorbid heroin and alcohol self-administration, to define the role of the ILNAshell circuit in drug seeking after polydrug use, and to determine how polydrug exposure alters intrinsic excitability of different neuronal populations in the infralimbic cortex and the regulation of neuronal excitability by 5-HT2A and MOR. These receptors are positioned to regulate excitability of cortical sub-circuits, with each predicted to culminate in increased ILNAshell output, and therefore increased inhibitory control over drug seeking. Information gained from this project will provide insight into whether heroin and alcohol polydrug use elicits neuroadaptations in cortical sub-circuits that are oppositional, additive, or otherwise distinct. It will also shed light onto how these circuits are regulated by 5-HT2A and MOR, both of which are druggable targets with known or emerging therapeutic applications for SUDs. Collectively, this will provide the groundwork for understanding how treatments can best be tailored to individuals with comorbid opioid and alcohol use.
项目摘要 阿片类药物使用障碍(OUD)通常与其他药物使用共病,酒精是最常见的共病之一。 吸毒然而,大多数关于OUD的基础研究都是在单一药物使用模型中进行的。电流 FDA批准的OUD治疗直接针对内源性阿片系统,无论是作为替代疗法, (e.g.丁丙诺啡、美沙酮)或对抗阿片样物质作用的拮抗剂(例如纳洛酮、纳洛酮)。这些 治疗确立了μ阿片受体(莫尔)作为OUD的主要治疗靶点。同样,阿片类药物具有 与酒精使用障碍(AUD)的病理生理学有关,纳洛酮用于治疗OUD和 和AUD,进一步强调了这些疾病之间的重叠机制。作为执行委员会的所在地 功能,前额叶皮层在抑制控制药物渴望和复发中起着不可或缺的作用。 患有物质使用障碍(SUD)的人表现出前额叶皮层的结构和功能变化, 并伴有认知功能缺陷。因此,前额叶皮层可能是阿片类药物诱导的神经元损伤的关键部位。 影响SUD严重程度的适应性。我的实验室已经确定了啮齿动物的边缘下(IL)前额皮质投射 核壳(IL-1 NA壳)作为海洛因寻求的重要限制。在IL皮质内, 中间神经元表达MORs,第5层锥体神经元(产生NA壳投射)表达 5-HT 2A受体。此外,我们最近已经证明了5-HT 2A激动剂减少阿片类药物的能力。 和寻求酒精(在单一药物使用模型中),并且这些影响在单次治疗后持续时间较长。 因此,5-HT 2A激动剂是OUD和AUD的新兴治疗剂类别,并且它们可以作用于 前额叶皮层微电路来引发这些效应。这项提议旨在研究这两个受体系统, 重点是前额叶皮层,在一个临床前模型的多药海洛因和酒精使用。该模型 合并慢性共病酒精暴露,在海洛因自我给药前开始并持续 在阿片类药物暴露期间。该项目的总体目标是确定5- HT 2A受体在海洛因和酒精自我给药后的药物寻求中的作用, 多药使用后药物寻求中的IL-16-NA壳回路,并确定多药暴露如何改变内在的 下边缘皮层中不同神经元群体的兴奋性和通过 5-HT 2A和莫尔。这些受体被定位以调节皮质子回路的兴奋性,其中每个受体都是神经元。 预计最终导致IL-16 β壳输出增加,因此增加了对药物的抑制控制, 寻找从该项目获得的信息将提供深入了解海洛因和酒精多药使用是否 在皮质子回路中的兴奋性神经适应是对立的、相加的或不同的。它还将 阐明了这些回路是如何被5-HT 2A和莫尔调节的,这两种都是可药物化的靶点, 已知或新兴的SUD治疗应用。总的来说,这将为以下方面奠定基础: 了解如何最好地为患有阿片类药物和酒精共病的个体量身定制治疗。

项目成果

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JAMIE PETERS其他文献

JAMIE PETERS的其他文献

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{{ truncateString('JAMIE PETERS', 18)}}的其他基金

Extinction Circuits Controlling Heroin Seeking
控制海洛因寻找的灭绝电路
  • 批准号:
    10357930
  • 财政年份:
    2018
  • 资助金额:
    $ 49.77万
  • 项目类别:
Extinction Circuits Controlling Heroin Seeking
控制海洛因寻找的灭绝电路
  • 批准号:
    9912742
  • 财政年份:
    2018
  • 资助金额:
    $ 49.77万
  • 项目类别:
Simulating Extinction Memory with Infralimbic DREADDs
使用下边缘 DREADD 模拟消退记忆
  • 批准号:
    8849885
  • 财政年份:
    2014
  • 资助金额:
    $ 49.77万
  • 项目类别:
Simulating Extinction Memory with Infralimbic DREADDs
使用下边缘 DREADD 模拟消退记忆
  • 批准号:
    8767607
  • 财政年份:
    2014
  • 资助金额:
    $ 49.77万
  • 项目类别:
Pre-existing Differences in BDNF and Fear Extinction
BDNF 和恐惧消退预先存在的差异
  • 批准号:
    7613259
  • 财政年份:
    2008
  • 资助金额:
    $ 49.77万
  • 项目类别:
Metabotropic glutamate receptors mediate cocaine relapse
代谢型谷氨酸受体介导可卡因复发
  • 批准号:
    6836990
  • 财政年份:
    2004
  • 资助金额:
    $ 49.77万
  • 项目类别:
Metabotropic glutamate receptors mediate cocaine relapse
代谢型谷氨酸受体介导可卡因复发
  • 批准号:
    6948176
  • 财政年份:
    2004
  • 资助金额:
    $ 49.77万
  • 项目类别:
Metabotropic glutamate receptors mediate cocaine relapse
代谢型谷氨酸受体介导可卡因复发
  • 批准号:
    7115921
  • 财政年份:
    2004
  • 资助金额:
    $ 49.77万
  • 项目类别:

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成瘾行为中谷氨酸稳态的神经元调节
  • 批准号:
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β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
  • 批准号:
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  • 财政年份:
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Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
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  • 批准号:
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  • 财政年份:
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  • 财政年份:
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食欲素和瘦素对 VTA 中进食和成瘾行为的调节
  • 批准号:
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  • 财政年份:
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Orexin and Leptin Regulation of Feeding and Addictive Behavior in the VTA
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  • 批准号:
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CBP Acetyltransferase Function in Addictive Behavior
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