PPARdelta receptors and alcohol use phenotypes

摘要 需要对酒精使用障碍(AUD)有新的神经生物学理解和治疗靶点。 AUD生物学研究进展表明，脂质信号是乙醇使用和戒断的关键调节因素 通过特殊的G蛋白偶联膜受体，运输蛋白，以及最近， 核转录因子。PPAR是由3个基因编码的脂质敏感转录因子(PPAR， PPAR、PPAR)，它们被确定为在燃料动态平衡的外周调节中发挥作用。PPAR和 PPAR因其抗成瘾作用而受到广泛关注。然而，更多的 强迫性酒精使用行为控制中脑PPAR受体亚型的大量表达 完全未知。在这里，我们测试了大脑过氧化物酶增殖物激活的最重要的假说。 受体-德尔塔亚型(PPAR)抑制酒精的强迫性使用和负性情绪退缩。研究 使用慢性间歇性乙醇蒸气暴露模型来诱导升级和抗厌恶的乙醇 摄取和戒断焦虑--以及类似易怒的行为，以产生对澳元的新的翻译见解。我们 将新型脑穿透性和可翻译的PPAR激动剂(KD3010，T3D-959)与脑受限和 位点特定的cre/lox条件PPAR敲除，以测试PPAR作用的因果作用和中心位点 强迫性酒精使用表型。由此产生的数据和新的基因和翻译相关 这种未被研究的PPARδ亚型的药理学工具将为细胞类型和 特定的解剖学机制研究，并可能导致对受强迫症影响的人进行干预 酗酒和其他形式的成瘾。

Abstract New neurobiological understanding of and therapeutic targets for alcohol use disorder (AUD) are needed. Advances in the biology of AUD indicate that lipid signaling is a key regulator of ethanol use and withdrawal behavior via specialized G-protein coupled membrane receptors, transport proteins, and, more recently, nuclear transcription factors. PPARs are lipid-sensing transcription factors encoded by 3 genes (PPAR, PPAR, PPAR) that were identified for their roles in peripheral regulation of fuel homeostasis. PPAR and PPAR have received intense attention for their anti-addiction-like actions. Yet, the central role of the more abundantly expressed brain PPARreceptor isotype in the control of compulsive alcohol use behaviors is entirely unknown. Here, we test the overarching hypothesis that brain peroxisome proliferator-activated receptors-delta subtype (PPAR) inhibits compulsive ethanol use and negative emotional withdrawal. Studies use the chronic intermittent ethanol vapor exposure model to elicit escalated and aversion-resistant ethanol intake and withdrawal anxiety- and irritability-like behavior to yield new translational insights into AUD. We combine novel brain-penetrant and translatable PPAR agonist (KD3010, T3D-959) and brain-restricted and site-specific cre/lox conditional PPAR knockouts to test the causal role and central sites of PPARaction in compulsive-like alcohol use phenotypes. The resulting data and novel genetic and translationally-relevant pharmacological tools for this understudied PPARδ isotype will lay the groundwork for cell type- and anatomically-specific mechanistic studies and may lead to interventions for people affected by compulsive alcohol use and other forms of addiction.