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

摘要 可卡因使用障碍药物治疗的发展落后于其他药物治疗。 神经精神疾病，强调需要新的目标。初步数据表明， 由环境富集产生的可卡因服用/寻求的保护性表型具有较少的视黄酸 神经元的信号传递，这是一个与成瘾高度相关的大脑区域。其他初步数据 显示增加视黄酸信号增加了丘脑核中的神经元放电和EPSC (NAc)壳和增加可卡因服用/寻求大鼠。抑制，减少维甲酸的一个方面 体内NAc中的信号传导减少神经元放电和可卡因摄取。目前的提案将产生 关于维甲酸信号如何赋予可卡因自身易感性的具体机制证据 局因此，该提议的总体假设是视黄酸的特定组分是由其代谢的。 NAc壳中的酸性信号传导途径控制对可卡因自我给药的敏感性/弹性， 代表了未来治疗可卡因依赖的有价值的新靶点。成功者， 该项目的完成将优先考虑维甲酸途径中的高质量“可药物化”目标， 可以开发并转化为临床实践的后续药理学开发。的 第一个目标将确定是否减少视黄酸合成的NAc壳单独赋予保护性 可卡因自我给药的表型。视黄酸合成酶Aldh 1a 1的表达将是 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，Aldh 1a 1抑制对行为、放电和突触的急性影响 将使用小分子抑制剂测试传播。第二个目标将决定相对 视黄酸受体（RAR）对过氧化物酶体增殖受体（PPARbeta/delta）信号传导影响 机制等AAV载体将用于敲低PPARbeta/delta或过表达RAR beta， 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测序一起使用以评估基因组方面。非基因组 方程的另一面将集中在神经元RNA的快速RA依赖性稳态突触可塑性 颗粒。该项目的最终结果将是一个急需的新的候选目标，用于治疗 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.