Assessing the role of corticostriatal circuitry in polysubstance use of fentanyl and methamphetamine using rat self-administration models

使用大鼠自我给药模型评估皮质纹状体回路在芬太尼和甲基苯丙胺多物质使用中的作用

基本信息

批准号：
10737092
负责人：
Susan Marie Ferguson
金额：
$ 48.2万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2023-06-15 至 2028-04-30
项目状态：
未结题

项目摘要

Project Summary Co-use of opioids (fentanyl, heroin) and methamphetamine is now highly prevalent across the U.S., and is associated with severe health risks, including HIV infection and overdose, and poorer treatment outcomes. Yet, the neural circuit alterations and accompanying behavioral changes associated with this polysubstance use are poorly defined, as are the similarities/differences between distinct patterns of opioid/methamphetamine co-use. Notably, the patterning of drug use can have enormous impacts on both circuit-wide brain adaptations and the development of addiction behaviors. Accordingly, delineating whether the outcomes that occur following distinct patterns of polysubstance use reflect the summation of each drug or are synergistic or distinct is particularly important, and likely critical for designing appropriate and long-lasting therapeutic interventions. To address this, we will use rat self-administration models of sequential (use of each substance on separate occasions) and simultaneous (use of both substances at the same time) polysubstance use of fentanyl and methamphetamine that mimic patterns of human consumption. Comparisons will also be made to groups that undergo self- administration of each substance singly. We will combine behavioral analysis with in vivo fiber photometry, ex vivo slice electrophysiology and targeted chemogenetic cellular manipulations to comprehensively map how striatal circuit activity is associated with addiction behaviors following different patterns of fentanyl and/or methamphetamine use. Striatal circuits (i.e., the NAc and its glutamate afferents from the PFC and its dopamine afferents from the VTA) will be examined as they are a key node of the cortico-basal ganglia-thalamic circuit that is well-established to regulate addiction-related behaviors of both opioids and stimulants. The overarching hypothesis of this work is that neural alterations in striatal circuitry will differ between sequential and simultaneous patterns of fentanyl and methamphetamine polysubstance use. In addition, we hypothesize that polysubstance use will produce synergistic and/or distinct circuit changes rather than summative changes compared to single substance use. Collectively, these results would support the idea that the patterning of substance use is particularly important for conferring the development of addiction-related behaviors. This work is significant as polysubstance use of opioids and methamphetamine is common and riskier, but vastly understudied. Our studies will help to address this gap and will provide an important and necessary foundation for ultimately understanding why polysubstance use drives continued drug use, and what neural cells and adaptations may be particularly relevant targets for therapies aimed at addressing polysubstance use.

项目概要阿片类药物（芬太尼、海洛因）和甲基苯丙胺的共同使用目前在美国非常普遍，并且与严重的健康风险有关，包括艾滋病毒感染和用药过量以及较差的治疗结果。然而，与这种多物质使用相关的神经回路改变和伴随的行为变化是定义不明确，阿片类药物/甲基苯丙胺共同使用的不同模式之间的相似/差异也是如此。值得注意的是，药物使用模式会对整个大脑的适应和大脑的适应产生巨大的影响。成瘾行为的发展。因此，描述以下不同的结果是否发生多物质使用模式反映了每种药物的总和，或者具有协同作用，或者是独特的对于设计适当且持久的治疗干预措施来说，这一点很重要，而且可能至关重要。为了解决这个问题，我们将使用顺序的大鼠自我给药模型（在不同的场合使用每种物质）和同时（同时使用两种物质）芬太尼和甲基苯丙胺的多种物质使用模仿人类消费模式。还将与经历自我干预的群体进行比较每种物质单独给药。我们将行为分析与体内光纤光度测量相结合，例如体内切片电生理学和靶向化学遗传学细胞操作，以全面绘制如何纹状体回路活动与芬太尼和/或不同模式的成瘾行为有关甲基苯丙胺的使用。纹状体回路（即 NAc 及其来自 PFC 的谷氨酸传入神经及其多巴胺来自 VTA 的传入神经）将受到检查，因为它们是皮质-基底节-丘脑回路的关键节点，已成熟地规范阿片类药物和兴奋剂的成瘾相关行为。首要的这项工作的假设是纹状体回路的神经改变在顺序和同时之间会有所不同芬太尼和甲基苯丙胺多物质的使用模式。此外，我们假设多物质与单个电路相比，使用将产生协同和/或独特的电路变化，而不是总结性变化物质的使用。总的来说，这些结果支持这样的观点：物质使用的模式是对于成瘾相关行为的发展尤其重要。这项工作的意义重大在于阿片类药物和甲基苯丙胺的多物质使用很常见且风险较高，但对此的研究却很少。我们的研究将有助于弥合这一差距，并为最终理解提供重要且必要的基础为什么多物质使用会导致持续吸毒，以及哪些神经细胞和适应性可能特别重要旨在解决多物质使用问题的治疗的相关目标。