Intersecting genetic risk for extreme cocaine self-administration with dopamine neurotransmission

极端可卡因自我给药与多巴胺神经传递的交叉遗传风险

• 批准号: 10525408
• 负责人: Jared R Bagley
• 金额: $ 14.01万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525408
• 关键词: Acute; Address; Affect; Animals; Autoreceptors; Biology; Brain; Candidate Disease Gene; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine use disorder; Complex; Data; Development; Disease; Dopamine; Exhibits; Fiber; Genes; Genetic; Genetic Risk; Genetic study; Goals; Health; Heritability; Human; Hybrids; Inbred Mouse; Inbred Strains Mice; Inbreeding; Individual; Intake; Intervention; Intravenous; Kinetics; Knock-out; Knowledge; Measures; Mediator; Methodology; Methods; Modeling; Modernization; Motivation; Mus; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Pathway interactions; Periodicity; Phase; Photometry; Positioning Attribute; Property; Regulation; Research; Risk; Risk Factors; Scanning; Self Administration; Signal Transduction; Slice; Societies; Techniques; Testing; Training; abuse liability; addiction; cocaine related behaviors; cocaine self-administration; cocaine use; disorder risk; dopaminergic neuron; drug of abuse; genetic analysis; genetic approach; genetic risk factor; genetic variant; high risk; improved; in vivo; insight; neuroadaptation; neurogenetics; neurotransmission; optogenetics; prevent; response; reuptake; risk variant; skills; trait; transmission process

Project summary/abstract Cocaine use disorder is a complexly determined, heritable trait that imposes significant harm on those afflicted and on society. Discovery of the genetic factors that influence cocaine use disorder risk is imperative for a comprehensive understanding of cocaine addiction neurobiology. In an ongoing study, we have characterized a large panel of inbred mouse lines for voluntary cocaine self-administration (IVSA). We are utilizing this approach to identify genes and allelic variants that influence cocaine self-administration, including Neuron- navigator-1 (Nav1), which has emerged as a candidate gene from our genetic analyses. Furthermore, inbred reference strains in the HMDP that are predisposed to take large amounts of cocaine represent polygenic models of extreme cocaine use and can be used to understand how risk variants collectively impact neurobiology to ultimately affect cocaine self-administration. The project proposed here will directly investigate the polygenic and single gene impact of genetic risk for extreme cocaine IVSA on mesolimbic dopamine neurotransmission, a key neurobiological function impacted by cocaine and other drugs of abuse. This project will provide training in fast-scan cyclic voltammetry, optogenetics and fiber photometry and will allow me to create a unique niche in addiction neurogenetics research. Aim 1 will investigate the influence of polygenic risk for extreme cocaine IVSA on dopamine neurotransmission in the Nucleus Accumbens (NAc) shell after acute application of cocaine. This aim may reveal genetic influences on basal and acute dopamine responses that underlie risk for dysregulated cocaine use. Aim 2 will investigate the influence of polygenic risk for extreme cocaine IVSA on neuroadaptations in dopamine transmission in the NAc following chronic cocaine IVSA exposure. This aim may reveal genetically determined adaptations of dopamine transmission that underlie escalated use after chronic exposure. Aim 3 will evaluate the causal effects of experimental changes in Nav1 expression on dopamine transmission at the single-gene level. This project will advance understanding of how genetics intersect with neurobiology to affect cocaine use. The training I will receive in conducting this project will broaden my skill set and allow me to more effectively investigate addiction neurogenetics.

项目摘要/摘要 可卡因使用障碍是一种复杂，可遗传的特征，对患者造成重大伤害 和社会。发现影响可卡因使用障碍风险的遗传因素对于 对可卡因成瘾神经生物学的全面理解。在正在进行的研究中，我们已经表征了 一大堆近交小鼠线，用于自愿自我管理（IVSA）。我们正在利用这个 识别影响可卡因自我给药的基因和等位基因变体的方法，包括神经元 Navigator-1（NAV1）已从我们的遗传分析中出现为候选基因。此外，近交 HMDP中的参考菌株易于服用大量可卡因代表多基因 极端可卡因的使用模型，可用于了解风险变体如何集体影响 神经生物学最终影响可卡因自我管理。这里提出的项目将直接调查 极端可卡因IVSA遗传风险对中唇胺多巴胺的多基因和单基因影响 神经传递，受可卡因和其他滥用药物影响的关键神经生物学功能。这个项目 将提供快速扫描的循环伏安法，光遗传学和光纤光度法的培训，并使我能够 在成瘾神经源性研究中创建独特的利基市场。 AIM 1将研究多基因风险的影响 急性后，对于多巴胺神经传递的极端可卡因IVSA 可卡因的应用。这个目标可能揭示了对基底和急性多巴胺反应的遗传影响 可卡因使用失调的风险是使用。 AIM 2将调查多基因风险的极端风险 可卡因IVSA在慢性可卡因IVSA之后，NAC中多巴胺传播中神经适应的可卡因IVSA 接触。这个目标可能揭示了多巴胺传播的遗传确定的适应 长期暴露后的使用升级。 AIM 3将评估NAV1实验变化的因果关系 在单基因水平的多巴胺传播上的表达。该项目将提高理解如何 遗传学与神经生物学相交，以影响可卡因的使用。我将在进行这个项目时获得的培训 将扩大我的技能，并让我更有效地研究成瘾神经遗传学。