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
• 负责人: Thomas Arthur Green
• 金额: $ 42.33万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425348
• 关键词: Acute; Affect; Behavior; Behavioral; Brain; Brain region; Cells; ChIP-seq; Chronic; Cocaine; Cocaine Dependence; Cocaine use disorder; Cytoplasmic Granules; DNA sequencing; Data; Development; Electrophysiology (science); Enzymes; Equation; Future; Gene Expression; Gene Transfer; Genetic; Genetic Transcription; Genomics; Knowledge; Lead; Measures; Messenger RNA; Molecular Biology; Neurobiology; Neuronal Plasticity; Neurons; Nucleus Accumbens; PPAR-beta; Pathway interactions; Peroxisome Proliferation; Pharmaceutical Preparations; Pharmacology; Phenotype; Predisposition; RNA; Rattus; Receptor Signaling; Regulation; Retinoic Acid Receptor; Saline; Side; Signal Pathway; Signal Transduction; Substance Use Disorder; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Translating; Tretinoin; Viral Vector; addiction; adeno-associated viral vector; base; behavioral phenotyping; chromatin immunoprecipitation; clinical practice; cocaine self-administration; druggable target; efficacious treatment; environmental enrichment for laboratory animals; experimental study; functional genomics; in vivo; inhibitor; knock-down; neuropsychiatry; neurotransmission; non-genomic; novel; overexpression; patch clamp; protein expression; receptor; resilience; small molecule; small molecule inhibitor; targeted treatment; therapeutic development; therapeutic target; vector

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.

抽象的 可卡因使用障碍药物治疗的发展落后于其他治疗方法 神经精神疾病，强调需要新的目标。初步数据表明，具有 环境富集产生的可卡因摄取/寻求的保护表型含有较少的视黄酸 伏隔核中的信号传导，伏隔核是与成瘾高度相关的大脑区域。额外的初步数据 表明增加视黄酸信号传导会增加伏隔核中的神经元放电和 EPSC (NAc) 外壳并增加大鼠对可卡因的摄取/寻找。相反，减少某一方面的视黄酸 体内 NAc 中的信号传导会减少神经元放电和可卡因摄入。当前提案将产生 关于视黄酸信号传导如何赋予可卡因自我敏感性的具体机制证据 行政。因此，该提案的总体假设是视黄酸的特定成分 NAc 壳中的酸信号通路控制对可卡因自我给药的敏感性/弹性，并且会 代表了未来治疗可卡因依赖的有价值的新目标。至此，成功的 该项目的完成将优先考虑视黄酸途径中的高质量“可成药”目标 随后的药物治疗开发可以开发并转化为临床实践。这 第一个目标是确定单独减少 NAc 壳中的视黄酸合成是否会产生保护作用 可卡因自我给药的表型。视黄酸合成酶 Aldh1a1 的表达为 在行为表型分析之前使用新型腺相关病毒载体（AAV）在体内敲低 电生理分析。接下来，Aldh1a1 抑制对行为、放电和突触的急性影响 将使用小分子抑制剂来测试传播。第二个目标将决定相对 视黄酸受体 (RAR) 与过氧化物酶体增殖受体 (PPARbeta/delta) 信号传导的影响 机制。 AAV 载体将用于敲低 PPARbeta/delta 或过表达 RARbeta 在易感大鼠中产生保护性行为和电生理表型。结果将 确定哪种竞争机制包含最有希望的治疗靶点。第三个目标 将确定大鼠 NAc 中视黄酸信号传导的相对基因组与非基因组影响。染色质 免疫沉淀将与 DNA 测序结合使用来评估基因组方面。非基因组 等式的一侧将重点关注神经元 RNA 的快速依赖于 RA 的稳态突触可塑性 颗粒。该项目的最终结果将是一个急需的新的治疗候选靶点 可卡因成瘾的发展。