Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety
食欲素调节酒精戒断焦虑中大脑奖赏-大脑应激系统相互作用
基本信息
- 批准号:10569020
- 负责人:
- 金额:$ 16.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AbstinenceAcuteAddictive BehaviorAddressAdultAffectAffective SymptomsAlcohol consumptionAlcohol dependenceAlcohol withdrawal syndromeAlcoholsAmericanAmygdaloid structureAnatomyAnimalsAnxietyAreaBehaviorBehavioralBrainBrain regionCNR1 geneCalcium SignalingCannabinoidsCessation of lifeChronicDataDependenceDepressed moodDevelopmentDiseaseDisinhibitionDopamineElectrophysiology (science)EndocannabinoidsFemaleFiberGene ExpressionGeneticGoalsHealthHumanImageIn VitroIndividualInhalationInvestigationMediatingMolecular BiologyMorbidity - disease rateMusNeurobiologyNeuronsNeuropeptidesNeurosciencesPharmacologyPhotometryPhysiologyQuality of lifeRattusReceptor ActivationRelapseResearchResearch TrainingRewardsRoleScientistSliceStressSystemTechniquesTestingTrainingUnited StatesVentral Tegmental AreaViralWithdrawalWorkaddictionalcohol effectalcohol researchalcohol responsealcohol use disorderanxiety-like behaviorcareercostdopaminergic neuronendocannabinoid signalingexperienceexperimental studyhypocretinimprovedin vivoindividual responseknock-downmalenegative affectneuralneuroadaptationneurobiological mechanismneurotransmissionorexin 1 receptorpharmacologicpresynapticreceptor expressionrecruitskillstherapeutically effectivetherapy developmenttreatment strategyvaporwithdrawal-induced anxiety
项目摘要
Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year
in the United States alone and costing the United States $249 billion annually. Humans with AUD often
experience negative affect during withdrawal (WD), and depressed mood and anxiety are positively correlated
with relapse during abstinence. The neurobiological mechanisms underlying an individual’s response to alcohol,
and his/her propensity to develop AUD, are not entirely understood. Acute and chronic alcohol alter
neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and chronic alcohol
also alters neurotransmission in the central amygdala (CeA), an area involved in increased anxiety during WD.
There is a functional connection between the VTA and CeA, and although each of these regions is important for
addictive behavior, the role of the connection between them in addictive behaviors is unknown. Our preliminary
data indicate that alcohol WD activates the VTA-CeA circuit in alcohol-dependent animals. The goal of this K01
proposal is to determine the mechanism underlying this circuit activation, as well as the contribution of the circuit
to increased anxiety-like behavior during WD. The overarching hypothesis of this proposal is that CeA-projecting
VTA dopamine (DA) neurons become activated during alcohol WD via an orexin 1 receptor (OX1R)-mediated
mechanism, and that activation of this circuit is critical in the development of dependence-associated increased
anxiety-like behavior during acute WD. To test this hypothesis, the proposal will utilize a combination of
anatomical, cellular, imaging, circuit-based and behavioral techniques. This proposal will provide a promising
young scientist with vital research training and professional development opportunities facilitated by experiments
that use an integrative approach to test the predictions that: (1) increased VTA-CeADA activity observed in vitro
during WD from chronic alcohol is mediated by OX1R/endocannabinoid (eCB) signaling, (2) that increased CeA
activity observed in vivo during WD from chronic alcohol is mediated by increased DA input from the VTA, and
(3) that VTA OX1R/eCB signaling mediates alcohol WD-induced anxiety-like behavior. The results of these
studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and
brain stress systems in addiction. This work may also inform development of treatment strategies for reducing
negative affective symptoms in individuals with AUD, leading to improvements in quality of life and health of
affected individuals, and decreasing morbidity associated with these disorders.
酒精使用障碍(AUD)影响着约1700万美国人,每年导致超过250万人死亡
仅在美国,每年就要花费美国2490亿美元。患有澳门氏症的人经常
戒断过程中的负性情绪(WD)与抑郁情绪、焦虑呈正相关
在禁欲期间复发。个体对酒精做出反应的神经生物学机制,
以及他/她患上AUD的倾向,还没有完全被理解。急、慢性酒精中毒
中脑皮质边缘回路的神经传递,包括腹侧被盖区(VTA)和慢性酒精
还改变了中央杏仁核(CEA)的神经传递,这是WD期间焦虑增加的一个区域。
VTA和CEA之间存在功能联系,尽管这些区域中的每一个都对
成瘾行为中,它们之间的联系在成瘾行为中的作用尚不清楚。我们的预赛
数据表明,酒精WD激活了酒精依赖动物的VTA-CEA回路。这款K01的目标是
建议确定这种电路激活的潜在机制,以及电路的贡献
导致WD期间焦虑样行为的增加。这一提议的首要假设是,CEA-投射
VTA多巴胺(DA)神经元在酒精WD时通过OX1R介导的激活
机制,而这个回路的激活在依赖相关增加的发展中是至关重要的
在急性WD期间出现焦虑样行为。为了验证这一假设,该提案将使用以下组合
解剖学、细胞学、成像、基于电路的和行为技术。这项建议将提供一个有希望的
通过实验获得重要研究培训和职业发展机会的年轻科学家
他们使用一种综合的方法来检验预测:(1)在体外观察到的VTA-CeADA活性增加
在慢性酒精引起的WD过程中,OX1R/内源性大麻素(ECB)信号介导,(2)CEA增加
在慢性酒精引起的WD期间观察到的活体活动是由VTA增加的DA输入介导的,并且
(3)VTA OX1R/ECB信号转导酒精WD诱导的焦虑样行为。这些研究的结果
研究将开辟神经科学研究的新途径,探索大脑奖励和
上瘾时的大脑压力系统。这项工作也可能为制定治疗策略提供信息,以减少
AUD患者的负性情感症状导致生活质量和健康的改善
受影响的个人,并减少与这些疾病相关的发病率。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Elizabeth Minor Avegno其他文献
Elizabeth Minor Avegno的其他文献
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{{ truncateString('Elizabeth Minor Avegno', 18)}}的其他基金
Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety
食欲素调节酒精戒断焦虑中大脑奖赏-大脑应激系统相互作用
- 批准号:
10302090 - 财政年份:2022
- 资助金额:
$ 16.36万 - 项目类别:
2020/2022 Alcohol and the Nervous System Gordon Research Conference & Gordon Research Seminar
2020/2022 酒精与神经系统戈登研究会议
- 批准号:
9912245 - 财政年份:2019
- 资助金额:
$ 16.36万 - 项目类别:
Brain Reward and Stress System Interactions in Alcohol Dependence
酒精依赖中的大脑奖励和压力系统相互作用
- 批准号:
9328415 - 财政年份:2017
- 资助金额:
$ 16.36万 - 项目类别:
Brain Reward and Stress System Interactions in Alcohol Dependence
酒精依赖中的大脑奖励和压力系统相互作用
- 批准号:
10264771 - 财政年份:2017
- 资助金额:
$ 16.36万 - 项目类别:
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