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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10737092
• 关键词: Address; Animal Model; Behavior; Behavioral; Biosensor; Brain; Calcium; Cells; Consumption; Corpus striatum structure; Cues; Development; Dopamine; Drug usage; Electrophysiology (science); Extinction; Fentanyl; Fiber; Foundations; Ganglia; Genetic; Glutamates; HIV Infections; Health; Heroin; Human; Image; Maps; Methamphetamine; Modeling; Monitor; Morbidity - disease rate; Motivation; Neurons; Nucleus Accumbens; Opioid; Outcome; Overdose; Pattern; Pharmaceutical Preparations; Photometry; Population; Prefrontal Cortex; Rattus; Research; Risk; Role; Self Administration; Slice; Stimulant; Synapses; Synaptic Transmission; Testing; Thalamic structure; Therapeutic Intervention; Time; Treatment outcome; Ventral Tegmental Area; Withdrawal; Work; addiction; behavioral economics; cell type; design; designer receptors exclusively activated by designer drugs; drug seeking behavior; fentanyl self-administration; fentanyl use; genetic manipulation; glutamatergic signaling; in vivo; methamphetamine use; mortality; neural; neural circuit; neuroadaptation; neuromechanism; neurotransmission; polysubstance use; substance use; targeted treatment; time use

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.

项目摘要 阿片类药物（芬太尼，海洛因）和甲基苯丙胺的共同使用现在在美国非常普遍，并且 与严重的健康风险相关，包括艾滋病毒感染和过量，以及较差的治疗结果。然而， 神经回路的改变和伴随的行为变化与这种多物质的使用有关， 定义不清，类阿片/甲基苯丙胺同时使用的不同模式之间的相似性/差异也是如此。 值得注意的是，药物使用的模式可以对整个大脑回路的适应性和神经元的功能产生巨大的影响。 成瘾行为的发展。因此，描述在不同的情况下发生的结果是否 多种药物的使用模式反映了每种药物的总和，或者是协同作用的，或者是不同的， 重要的，并可能是设计适当和持久的治疗干预的关键。为了解决这个问题， 我们将使用大鼠自我给药模型的顺序（使用每种物质在不同的场合）和 同时（同时使用两种物质）使用芬太尼和甲基苯丙胺 模仿人类的消费模式。还将与经历自我- 每种物质单独给药。我们将联合收割机行为分析与体内纤维光度测定相结合， 体内切片电生理学和有针对性的化学遗传细胞操作，以全面映射如何 纹状体回路活动与不同模式的芬太尼和/或 使用冰毒纹状体回路（即，NAc及其来自PFC及其多巴胺的谷氨酸传入 来自VTA的传入），因为它们是皮质-基底神经节-丘脑回路的关键节点， 是公认的调节阿片类药物和兴奋剂的成瘾相关行为。总体 这项工作的假设是，纹状体回路中的神经改变在顺序和同时之间是不同的 芬太尼和甲基苯丙胺多种物质的使用模式。此外，我们假设多物质 使用将产生协同和/或不同的电路变化，而不是与单一电路相比的总结性变化。 物质使用。总的来说，这些结果将支持这样的观点，即物质使用的模式是 这对成瘾相关行为的发展尤为重要。这项工作意义重大， 类阿片和甲基苯丙胺的多种物质使用很常见，风险也更大，但对这一问题的研究远远不够。我们的研究 将有助于解决这一差距，并将为最终理解提供重要和必要的基础 为什么多种物质的使用会导致持续的药物使用，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。