Endocannabinoid Mechanisms in the Pathophysiology of Alcohol Use Disorders
酒精使用障碍病理生理学中的内源性大麻素机制
基本信息
- 批准号:9402717
- 负责人:
- 金额:$ 41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:2-arachidonylglycerol2-arachidonylglycerol signalingAbstinenceAcuteAffectiveAffective SymptomsAlcohol consumptionAlcohol withdrawal syndromeAlcoholsAmygdaloid structureAntidepressive AgentsAnxietyBehaviorBehavioralBiochemical GeneticsBrainCNR1 geneCell NucleusCellsCharacteristicsChronicCorticotropin-Releasing HormoneCuesDataDiseaseElectrophysiology (science)ElementsEndocannabinoidsEnvironmentFeelingFunctional disorderGenerationsGlutamatesHumanHyperactive behaviorIndividualInsula of ReilLinkMediatingMental DepressionModelingMood DisordersMoodsNegative ReinforcementsNeuronsPatientsPharmaceutical PreparationsPharmacological TreatmentPharmacologyPhenotypePhysiologicalPlayPopulationPrevalenceProcessRecruitment ActivityRegulationRelapseRodentRoleSelective Serotonin Reuptake InhibitorSignal TransductionSpecificityStructure of terminal stria nuclei of preoptic regionSubstance abuse problemSymptomsSynapsesSynaptic plasticitySystemTestingTherapeuticTimeadverse outcomeaffective disturbancealcohol abstinencealcohol seeking behavioralcohol use disorderassociated symptombasedepressive symptomsdrinkingdriving forceeffective therapyendocannabinoid signalingin vivoinsightmouse modelnegative affectneural circuitneuroimaging markerneuroregulationnovelnovel strategiesoptogeneticspatch clamppreventresponsewithdrawal-induced anxiety
项目摘要
PROJECT SUMMARY
Alcohol use disorders (AUDs) manifest from a convergence of characteristics of the individual, the
environment, and the alcohol itself. The affective disturbances associated with alcohol withdrawal are
examples of this convergence and represent a critical barrier to successful treatment. Reduction of these
affective disturbances has been suggested to represent an important conceptual approach to reduce negative
reinforcement-based alcohol intake in dependent individuals. However, treatment of these affective
disturbances is complicated by data indicating reduced efficacy of antidepressants such as selective-serotonin
reuptake inhibitors (SSRIs) in patients with AUDs, and that these traditional treatments can actually increase
alcohol intake in some people;; thus, alternate non-monoamine-based treatment approaches for affective
symptoms associated with AUDs are critically needed. Here we will test the novel hypothesis that
pharmacological augmentation of endogenous cannabinoid signaling could represent an effective treatment for
negative affective states associated with alcohol withdrawal including anxiety and depression, and could
thereby facilitate abstinence in patients with AUDs. We will test the overall hypothesis that 2-
arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling reduces anxiety and depressive-like
behaviors associated with acute and protracted alcohol withdrawal in a mouse model of voluntary alcohol
consumption. To interrogate the underlying mechanism of this effect, we will test the hypothesis that insula
cortical-extended amygdala circuits are hyperactive during alcohol withdrawal and that over activation of this
circuit is causally linked to the affective phenotypes observed during alcohol withdrawal. Finally, we will test the
hypothesis that 2-AG-mediated inhibition of insula-extended amygdala circuit activity represents a key
mechanism by which endocannabinoid signaling reduces alcohol withdrawal-induced anxiety and depressive-
like behaviors. These data could provide new insight into the neural circuit mechanisms responsible for
generating negative affective states associated with alcohol withdrawal, and reveal novel neuromodulatory
mechanisms capable of counteracting these processes. If successful, these studies could support
advancement of 2-AG-based pharmacological treatments for AUDs and co-morbid affective disorders.
项目摘要
酒精使用障碍(AUDs)表现为个体特征的融合,
环境,酒精本身。 与酒精戒断相关的情感障碍是
这种融合的例子,并代表了成功治疗的关键障碍。减少这些
情感障碍被认为是减少消极情绪的一种重要的概念性方法。
强化-依赖性个体基于酒精摄入量。然而,这些情感治疗,
有数据表明,抗抑郁药(如选择性5-羟色胺)的疗效降低,
再摄取抑制剂(SSRIs)在AUD患者中的作用,这些传统治疗实际上可以增加
一些人的酒精摄入量;因此,替代的非单胺-β-内酰胺酶为基础的治疗方法,
与AUD相关的症状是非常需要的。 在这里,我们将测试新的假设,
内源性大麻素信号传导的药理学增强可能代表了对
与酒精戒断相关的消极情感状态,包括焦虑和抑郁,
从而促进AUDs患者的禁欲。我们将检验2-羟色胺的总体假设,
花生四烯酰甘油(2-NAG)-β-内酰胺酶介导的内源性大麻素信号转导减少焦虑和抑郁-类阿片样
在自愿饮酒的小鼠模型中与急性和长期酒精戒断相关的行为
为了探究这种效应的潜在机制,我们将检验以下假设:
皮质-杏仁核延伸回路在酒精戒断时过度活跃,
回路与酒精戒断过程中观察到的情感表型有因果关系。最后,我们将测试
假设2-β AG-β介导的β-β延伸杏仁核回路活性的抑制是一个关键,
内源性大麻素信号减少酒精戒断引起的焦虑和抑郁的机制
比如行为 这些数据可以为神经回路机制提供新的见解,
产生与酒精戒断相关的负面情感状态,并揭示了新的神经调节
如果成功的话,这些研究可以支持
基于2-乙酰氨基葡萄糖的药物治疗AUD和共病情感障碍的进展。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Sachin Patel其他文献
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{{ truncateString('Sachin Patel', 18)}}的其他基金
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
10438780 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
10549686 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
10645220 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Annual Cannabinoid Research Society Symposium on the Cannabinoids
年度大麻素研究会大麻素研讨会
- 批准号:
10316952 - 财政年份:2021
- 资助金额:
$ 41万 - 项目类别:
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
9913026 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
10202438 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Central Amygdala Glutamatergic Circuits in Fear Learning and Extinction
中央杏仁核谷氨酸回路在恐惧学习和消退中的作用
- 批准号:
10013294 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
2019 Cannabinoid Function in the CNS GRC & GRS
2019 大麻素在 CNS GRC 中的功能
- 批准号:
9891042 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Endocannabinoid Mechanisms in the Pathophysiology of Alcohol Use Disorders
酒精使用障碍病理生理学中的内源性大麻素机制
- 批准号:
10587760 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
Endocannabinoid Mechanisms in the Pathophysiology of Alcohol Use Disorders
酒精使用障碍病理生理学中的内源性大麻素机制
- 批准号:
10165419 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别: