Plasticity of GABA input to VTA dopamine neurons in opioid use disorders
阿片类药物使用障碍中 VTA 多巴胺神经元 GABA 输入的可塑性
基本信息
- 批准号:10512049
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-10-01 至 2025-09-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAbstinenceAffectAffinity ChromatographyAgingAllelesAreaAstrocytesAttentionBehaviorBehavioralBioinformaticsBrainBreedingCell NucleusChestClinicalCodeCre lox recombination systemCuesDNADataDependovirusDevelopmentDiseaseDisinhibitionElectrophysiology (science)Enterobacteria phage P1 Cre recombinaseFamily memberFemaleFentanylGene ExpressionGeneral PopulationGenesGeneticGleanHypothalamic structureIndividualInjectionsIntakeKnock-outKnowledgeLabelLateralLinkLoxP-flanked alleleMaintenanceMeasuresMediatingMolecularMusNeuronsNeurotensinNeurotensin ReceptorsNeurotransmittersNociceptionNuclearNucleic AcidsNucleus AccumbensOpioidOpioid ReceptorOverdosePainPain managementPathway interactionsPeptidesPharmaceutical PreparationsPhysiologicalProceduresPropertyPsychological reinforcementPublic HealthQuality of lifeRNARattusReceptor SignalingRecording of previous eventsRelapseRibosomesRiskRoleSelf AdministrationSignal TransductionSiteSliceSourceSuicideSynapsesSynaptic TransmissionSynaptic plasticitySystemTechniquesTestingTitrationsTranslatingVentral Tegmental AreaVeteransViralVirusWithdrawalWorkWritingadverse outcomealdehyde dehydrogenase 1analogcell typechronic pain managementdesigner receptors exclusively activated by designer drugsdopamine transporterdopaminergic neurondrug reinforcementepigenomicsexperienceexperimental studygamma-Aminobutyric Acidgene interactionimprovedinnovationmalemouse geneticsmu opioid receptorsneuronal excitabilityneurophysiologynew therapeutic targetnovelopioid abuseopioid epidemicopioid exposureopioid useopioid use disorderoptogeneticspatch clampprescription opioidpresynapticreceptorremifentanilside effectsuicidal risktooltranscriptometranscriptomicstreatment strategyvesicular GABA transporter
项目摘要
Despite their dangers, the number of opioid prescriptions written for veterans has increased sharply since
2000, and veterans are more prone than the general population to both suicide and the development of use
disorders following opioid treatment. Target receptors for opioids are widely expressed throughout the brain
and periphery, but their reinforcing properties are largely mediated by their action in mesocorticolimbic areas
such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). In the VTA, activation of
presynaptic mu-opioid receptors is known to blunt release of the inhibitory neurotransmitter GABA, thus
“disinhibiting” dopamine neuron activity. Preliminary work has established that the modulatory peptide
neurotensin can activate presynaptic neurotensin 1 receptors (NtsR1) to enhance GABA release in the VTA.
While this novel form of synaptic plasticity would be expected to directly counteract the effects of opioids, it is
not known how repeated opioid exposure interacts with neurotensin effects on GABA signaling. Opioids and
neurotensin are both known to modulate pain; however, there are significant gaps in our knowledge of how
these compounds interact at the synaptic and circuit level in the VTA to affect drug reinforcement. Improved
treatments for opioid use disorders are desperately needed, both for the general population but also for aging
veterans that will increasingly develop painful conditions that require long-term treatment. The proposed
studies are necessary to determine the feasibility of targeting the neurotensin system to modulate
reinforcement and relapse in individuals that no longer can control their opioid intake.
We will combine brain slice electrophysiology and cell type-specific molecular techniques with self-
administration of the opioid remifentanil in mice to explore these issues. The use of operant self-administration
in mice offers several key advantages: mice are able to titrate their intake based on individual sensitivity, and
using mice instead of rats opens up the powerful tools of mouse genetics (i.e., Cre-lox technology) to
experimental manipulations. The hypothesis to be tested is that a history of remifentanil self-administration
decreases neurotensin-induced enhancement of GABA release in the NAc VTA circuit, removing a critical
break on dopamine neuron excitability during drug intake to increase reinforcement. Experiments in Aim 1 will
identify the sensitivity of individual GABA inputs in the VTA to neurotensin, and determine how plasticity is
affected by remifentanil self-administration as well as following a forced abstinence. Experiments in Aim 2 will
use chemogenetics to activate specific GABA inputs to determine their effect on remifentanil self-administration
behavior and cue responding following a forced abstinence. A novel cell type-specific neurotensin receptor
knockout will provide additional information on the role of specific cell types on opioid self-administration.
Experiments in Aim 3 will use a discovery approach to determine transcriptomic and epigenomic alterations
following remifentanil self-administration in single cell types of the VTA. This will be done with several novel
NuTRAP (Nuclear Tagging and Translating Ribosome Affinity Purification) mouse lines under the control of Cre
recombinase that allow for labeling and isolation of both DNA and RNA from specific cell types. Improved
strategies are desperately needed to improve the quality of life for veterans at risk of adverse consequences
following opioid treatment. Data obtained will delineate the behavioral and physiological interactions between
GABA input to the VTA, neurotensin signaling, and opioid exposure, and identify novel gene and receptor
targets for exploration as treatments for opioid use disorders.
尽管存在危险,但此后为退伍军人开出的阿片类药物处方数量急剧增加
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Michael J Beckstead其他文献
Michael J Beckstead的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Michael J Beckstead', 18)}}的其他基金
Plasticity of GABA input to VTA dopamine neurons in opioid use disorders
阿片类药物使用障碍中 VTA 多巴胺神经元 GABA 输入的可塑性
- 批准号:
10259310 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Effects of dietary restriction on age-related neurophysiological adaptations: from behavior to single dopaminergic neurons
饮食限制对年龄相关神经生理适应的影响:从行为到单个多巴胺能神经元
- 批准号:
9240155 - 财政年份:2016
- 资助金额:
-- - 项目类别:
The role of dendrodendritic dopamine neurotransmission in methamphetamine abuse
树突状多巴胺神经传递在甲基苯丙胺滥用中的作用
- 批准号:
8440057 - 财政年份:2013
- 资助金额:
-- - 项目类别:
The role of dendrodendritic dopamine neurotransmission in methamphetamine abuse
树突状多巴胺神经传递在甲基苯丙胺滥用中的作用
- 批准号:
8617261 - 财政年份:2013
- 资助金额:
-- - 项目类别:
The role of dendrodendritic dopamine neurotransmission in methamphetamine abuse
树突状多巴胺神经传递在甲基苯丙胺滥用中的作用
- 批准号:
9187450 - 财政年份:2013
- 资助金额:
-- - 项目类别:
The role of dendrodendritic dopamine neurotransmission in methamphetamine abuse
树突状多巴胺神经传递在甲基苯丙胺滥用中的作用
- 批准号:
9085629 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7406089 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7254296 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7615534 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Methamphetamine Effects on Dendrodendritic Dopamine Transmission in the VTA
甲基苯丙胺对 VTA 树突状多巴胺传递的影响
- 批准号:
7816734 - 财政年份:2007
- 资助金额:
-- - 项目类别:
相似海外基金
StuDy AimED at Increasing AlCohol AbsTinEnce (DEDICATE)
旨在提高酒精戒断率的研究(奉献)
- 批准号:
10577022 - 财政年份:2023
- 资助金额:
-- - 项目类别:
A Controlled Study of Extended Cannabis Abstinence in Major Depression
重度抑郁症患者长期吸食大麻的对照研究
- 批准号:
478313 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Operating Grants
Exercised-induced modulation of insular cortex microcircuitry during alcohol abstinence
戒酒期间运动诱导的岛叶皮质微电路调节
- 批准号:
10748763 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Prapela™ SVS: A cost-effective stochastic vibrotactile stimulation device toimprove the clinical course of infants with neonatal abstinence syndrome.
Prapela™ SVS:一种经济高效的随机振动触觉刺激装置,可改善患有新生儿戒断综合征的婴儿的临床过程。
- 批准号:
10837421 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Enforced alcohol abstinence: does it reduce reoffending?
强制戒酒:会减少再犯罪吗?
- 批准号:
ES/X003566/1 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Fellowship
Neurobiological impact of acute digital media abstinence among drug using college students
吸毒大学生急性数字媒体戒断的神经生物学影响
- 批准号:
10677380 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Single-cell whole brain imaging of nicotine intoxication, dependence, and abstinence
尼古丁中毒、依赖和戒断的单细胞全脑成像
- 批准号:
10588509 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Understanding recovery from alcohol use disorder: Longitudinal observation of two voluntary temporary abstinence periods
了解酒精使用障碍的恢复:两个自愿临时戒酒期的纵向观察
- 批准号:
10740677 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Sleep Disturbances During Cocaine Abstinence, Dopamine Adaptations, and Motivation for Cocaine
可卡因戒断期间的睡眠障碍、多巴胺适应和可卡因动机
- 批准号:
10681668 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence
转录适应导致长期戒酒的依赖性大鼠对酒精的渴求加剧
- 批准号:
10540014 - 财政年份:2022
- 资助金额:
-- - 项目类别: