Retinoic acid signaling: a novel factor for addiction-related behavior

摘要 可卡因使用障碍的药物疗法的发展落后于其他药物的治疗。 神经精神疾病，强调需要新的目标。初步数据显示，患有老年痴呆症的老鼠 环境浓缩产生的可卡因摄取/寻找保护性表型维甲酸较少 伏隔核中的信号，这是一个与成瘾密切相关的大脑区域。其他初步数据 结果表明，维甲酸信号的增加增加了伏隔核神经元的放电和EPSCs (NAC)壳，并增加大鼠的可卡因摄取/寻找。相反，减少维甲酸的一个方面 体内NAC中的信号减少了神经元的放电和可卡因的摄取。目前的提案将产生 关于维甲酸信号如何使自身对可卡因易感性的特定机制证据 行政管理。因此，这一提议的总体假设是维甲酸的特定成分 NAC外壳中的酸性信号通路控制着对可卡因自我给药的敏感性/弹性和Will 代表了未来治疗可卡因依赖的有价值的新目标。因此，成功的 该项目的完成将优先考虑维甲酸途径中的高质量“可用药”靶点 可以开发并转化为临床实践的后续药物治疗开发。这个 第一个目标是确定减少NAC外壳中维甲酸的合成是否单独提供了一种保护性 可卡因自我给药的表型。维甲酸合成酶Aldh1a1的表达 在体内使用新型腺相关病毒载体(AAV)在行为表型和 电生理分析。接下来，Aldh1a1抑制对行为、放电和突触的急性影响 传输将使用一种小分子抑制剂进行测试。第二个目标将决定相对的 视黄酸受体(RAR)与过氧化物酶体增殖性受体(PPARbeta/Delta)信号转导的关系 机械装置。AAV载体将用于下调PPARbeta/Delta或过表达RARbeta到 在易感大鼠中创造保护性的行为和电生理表型。结果将会是 确定哪种相互竞争的机制包含最有希望的治疗靶点。第三个目标 将确定维甲酸信号在大鼠NAC中的相对基因组和非基因组影响。染色质 免疫沉淀法将与DNA测序一起用于评估基因组方面。非基因组学 方程式的另一边将关注神经元RNA对RA依赖的稳态突触的快速可塑性 颗粒。这个项目的最终结果将是一个亟需的治疗新候选靶点 可卡因成瘾的发展。

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.