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: 10177986
• 负责人: Thomas Arthur Green
• 金额: $ 44.08万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177986
• 关键词: Acute; Affect; Behavior; Behavioral; Brain; Brain region; Cells; ChIP-seq; Chronic; Cocaine; Cocaine Dependence; Cytoplasmic Granules; DNA sequencing; Data; Development; Disease; 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; Self Administration; 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; cocaine use; druggable target; efficacious treatment; environmental enrichment for laboratory animals; experimental study; functional genomics; in vivo; inhibitor/antagonist; 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.

摘要