Retinoic acid signaling: a novel factor for addiction-related behavior
视黄酸信号传导:成瘾相关行为的新因素
基本信息
- 批准号:10177986
- 负责人:
- 金额:$ 44.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectBehaviorBehavioralBrainBrain regionCellsChIP-seqChronicCocaineCocaine DependenceCytoplasmic GranulesDNA sequencingDataDevelopmentDiseaseElectrophysiology (science)EnzymesEquationFutureGene ExpressionGene TransferGeneticGenetic TranscriptionGenomicsKnowledgeLeadMeasuresMessenger RNAMolecular BiologyNeurobiologyNeuronal PlasticityNeuronsNucleus AccumbensPPAR-betaPathway interactionsPeroxisome ProliferationPharmaceutical PreparationsPharmacologyPhenotypePredispositionRNARattusReceptor SignalingRegulationRetinoic Acid ReceptorSalineSelf AdministrationSideSignal PathwaySignal TransductionSubstance Use DisorderSynapsesSynaptic TransmissionSynaptic plasticitySystemTechniquesTestingTranslatingTretinoinViral Vectoraddictionadeno-associated viral vectorbasebehavioral phenotypingchromatin immunoprecipitationclinical practicecocaine self-administrationcocaine usedruggable targetefficacious treatmentenvironmental enrichment for laboratory animalsexperimental studyfunctional genomicsin vivoinhibitor/antagonistknock-downneuropsychiatryneurotransmissionnon-genomicnoveloverexpressionpatch clampprotein expressionreceptorresiliencesmall moleculesmall molecule inhibitortargeted treatmenttherapeutic developmenttherapeutic targetvector
项目摘要
ABSTRACT
The development of pharmacotherapeutics for cocaine use disorder has lagged behind treatments for other
neuropsychiatric conditions, emphasizing the need for new targets. Preliminary data suggest that rats with a
protective phenotype for cocaine taking/seeking produced by environmental enrichment have less retinoic acid
signaling in the nucleus accumbens, a brain region highly implicated in addiction. Additional preliminary data
show that increasing retinoic acid signaling increases neuronal firing and EPSCs in the nucleus accumbens
(NAc) shell and increases cocaine taking/seeking in rats. Inversely, decreasing one aspect of retinoic acid
signaling in the NAc in vivo decreases neuronal firing and cocaine taking. The current proposal will generate
specific mechanistic evidence regarding how retinoic acid signaling confers susceptibility to cocaine self-
administration. Accordingly, the overall hypothesis of this proposal is that specific components of the retinoic
acid signaling pathway in the NAc shell control susceptibility/resilience to cocaine self-administration and will
represent valuable novel targets for the future treatment of cocaine dependence. Thus, the successful
completion of this project will prioritize high-quality “druggable” targets in the retinoic acid pathway for
subsequent pharmacotherapeutic development that can be developed and translated into clinical practice. The
first aim will determine if decreasing retinoic acid synthesis in the NAc shell alone confers a protective
phenotype for cocaine self-administration. Expression of the retinoic acid synthesis enzyme Aldh1a1 will be
knocked down in vivo using a novel adeno-associated viral vector (AAV) prior to behavioral phenotyping and
electrophysiological analysis. Next, the acute effects of Aldh1a1 inhibition on behavior, firing, and synaptic
transmission will be tested using a small-molecule inhibitor. The second aim will determine the relative
influence of retinoic acid receptor (RAR) vs. peroxisome proliferative receptor (PPARbeta/delta) signaling
mechanisms. AAV vectors will be used to either knock down PPARbeta/delta or overexpress RARbeta to
create a protective behavioral and electrophysiological phenotype in susceptible rats. The results will
determine which of the competing mechanisms contains the most promising therapeutic target. The third aim
will determine the relative genomic vs. non-genomic influence of retinoic acid signaling in rat NAc. Chromatin
immunoprecipitation will be employed with DNA sequencing to assess the genomic aspect. The non-genomic
side of the equation will focus on rapid RA-dependent homeostatic synaptic plasticity from neuronal RNA
granules. The final result of this project will be a much-needed novel candidate target for therapeutic
development for cocaine addiction.
摘要
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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Thomas Arthur Green其他文献
Thomas Arthur Green的其他文献
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{{ truncateString('Thomas Arthur Green', 18)}}的其他基金
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
- 批准号:
10430263 - 财政年份:2020
- 资助金额:
$ 44.08万 - 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
- 批准号:
10663801 - 财政年份:2020
- 资助金额:
$ 44.08万 - 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
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10271267 - 财政年份:2020
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Gpr12: a novel factor for addiction and mental health
Gpr12:成瘾和心理健康的新因素
- 批准号:
9813292 - 财政年份:2019
- 资助金额:
$ 44.08万 - 项目类别:
Retinoic acid signaling: a novel factor for addiction-related behavior
视黄酸信号传导:成瘾相关行为的新因素
- 批准号:
10425348 - 财政年份:2018
- 资助金额:
$ 44.08万 - 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
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8576928 - 财政年份:2013
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$ 44.08万 - 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
- 批准号:
8917636 - 财政年份:2013
- 资助金额:
$ 44.08万 - 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
- 批准号:
9250231 - 财政年份:2013
- 资助金额:
$ 44.08万 - 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
- 批准号:
8843055 - 财政年份:2013
- 资助金额:
$ 44.08万 - 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
- 批准号:
9039670 - 财政年份:2013
- 资助金额:
$ 44.08万 - 项目类别:
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