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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要可卡因使用障碍是一种复杂的、可遗传的特征，对受影响者造成重大伤害以及关于社会。发现影响可卡因使用障碍风险的遗传因素对于全面了解可卡因成瘾神经生物学。在一项正在进行的研究中，我们已经描述了一大组用于自愿可卡因自我给药（IVSA）的近交系小鼠品系。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异的方法，包括神经元 navigator-1 (Nav1)，它是我们的遗传分析中的候选基因。此外，近交系 HMDP 中倾向于吸食大量可卡因的参考菌株代表多基因可卡因极端使用模型，可用于了解风险变异如何共同影响神经生物学最终影响可卡因的自我给药。这里提出的项目将直接调查极端可卡因 IVSA 遗传风险对中脑边缘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循环伏安法、光遗传学和光纤光度法方面的培训，并使我能够在成瘾神经遗传学研究中创造独特的利基。目标 1 将调查多基因风险的影响急性可卡因 IVSA 对伏核 (NAc) 壳中多巴胺神经传递的影响可卡因的应用。这一目标可能揭示遗传对基础和急性多巴胺反应的影响，是可卡因使用失调风险的根源。目标 2 将研究多基因风险对极端情况的影响可卡因 IVSA 对慢性可卡因 IVSA 后 NAc 中多巴胺传递的神经适应接触。这一目标可能揭示多巴胺传递的基因决定的适应性长期接触后逐步增加使用。目标 3 将评估 Nav1 实验变化的因果影响单基因水平上多巴胺传递的表达。该项目将加深人们对如何遗传学与神经生物学交叉影响可卡因的使用。我在执行这个项目时将接受的培训将扩大我的技能范围，使我能够更有效地研究成瘾神经遗传学。