The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
Biol Psychiatry. 2019 Jun 15;85(12):1036-1045. doi: 10.1016/j.biopsych.2019.02.006. Epub 2019 Feb 13.
The endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-α by the endocannabinoid congener N-palmitoylethanolamine (PEA) regulates pathophysiological systems (e.g., inflammation, oxidative stress) and induces peripheral biosynthesis of allopregnanolone, a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders. However, effects of PPAR-α on emotional behavior are poorly understood.
We studied the impact of PPAR-α activation on emotional behavior in a mouse model of posttraumatic stress disorder. Neurosteroid levels before and after PEA treatment were measured by gas chromatography-mass spectrometry in relevant brain regions of socially isolated versus group-housed mice exposed to the contextual fear conditioning test, elevated plus maze test, forced swim test, and tail suspension test. Neurosteroidogenic enzyme levels were quantified in hippocampus by Western blot.
PEA administered in a model of conditioned contextual fear reconsolidation blockade facilitated fear extinction and fear extinction retention and induced marked antidepressive- and anxiolytic-like effects in socially isolated mice with reduced brain allopregnanolone levels. These effects were mimicked by the PPAR-α synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-α deletion, PPAR-α antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-α, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels.
This evidence supports a previously unknown role for PPAR-α in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.
内源性大麻素和神经甾体系统调节情绪和应激反应。内源性大麻素类似物 N-棕榈酰乙醇胺（PEA）激活过氧化物酶体增殖物激活受体（PPAR）-α，调节病理生理系统（如炎症、氧化应激），并诱导全异戊烯醇酮的外周生物合成，全异戊烯醇酮是一种γ-氨基丁酸能神经甾体，与心境障碍有关。然而，PPAR-α 对情绪行为的影响知之甚少。
我们在创伤后应激障碍的小鼠模型中研究了 PPAR-α 激活对情绪行为的影响。通过气相色谱-质谱法测量社交隔离与群居小鼠在暴露于情境恐惧条件反射测试、高架十字迷宫测试、强迫游泳测试和悬尾测试后，PEA 治疗前后相关脑区的神经甾体水平。通过 Western blot 定量海马中的神经甾体生成酶水平。
在条件性情境恐惧再巩固阻断模型中给予 PEA 可促进恐惧消退和恐惧消退保留，并在社交隔离小鼠中诱导明显的抗抑郁和抗焦虑样作用，同时降低大脑全异戊烯醇酮水平。这些作用被 PPAR-α 合成激动剂非诺贝特和 GW7647 模拟，被 PPAR-α 缺失、PPAR-α 拮抗剂和神经甾体酶抑制剂阻止。行为改善与 PEA 诱导的 PPAR-α 上调、神经甾体生成酶表达和皮质边缘全异戊烯醇酮水平的正常化相关。
这一证据支持了 PPAR-α 在行为调节中的一个先前未知的作用，并为治疗神经精神病理疾病提供了新策略，包括创伤后应激障碍和重度抑郁症，这些疾病的特征是神经甾体生成不足。
