Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior
Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior
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DOI：
10.1016/j.biopsych.2019.02.006
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发表时间：
2019-06-15
影响因子：
10.6
通讯作者：
Pinna, Graziano
中科院分区：
文献类型：
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作者：
Locci, Andrea;Pinna, Graziano
背景：内源性大麻素和神经类固醇系统调节情绪和应激反应。内源性大麻素同系物N-棕榈酰乙醇胺（PEA）对过氧化物酶体增殖物激活受体（PPAR）-α的激活调节病理生理系统（例如，炎症、氧化应激）并诱导别孕烯醇酮（一种涉及情绪障碍的γ-氨基丁酸能神经类固醇）的外周生物合成。然而，PPAR-alpha对情绪behaviors.METHODS的影响知之甚少：我们研究了创伤后应激障碍小鼠模型中PPAR-alpha激活对情绪行为的影响。通过气相色谱-质谱法测定PEA治疗前后社交隔离与群体圈养小鼠相关脑区的神经类固醇水平，这些小鼠暴露于情境恐惧条件反射试验、高架十字迷宫试验、强迫游泳试验和悬尾试验。Western blot.RESULTS：PEA管理的一个模型的条件上下文恐惧再巩固封锁促进恐惧消退和恐惧消退保留和诱导显着的抗抑郁和抗焦虑样作用在社会隔离的小鼠脑allopregnanolone水平降低。这些作用被PPAR-alpha合成激动剂非诺贝特和GW 7647模拟，并被PPAR-alpha缺失、PPAR-alpha拮抗剂和神经类固醇酶抑制剂阻止。行为改善与PEA诱导的PPAR-alpha，神经甾体生成酶的表达上调，和corticolimbic allopregnanolone levels.CONCLUSIONS的正常化：这一证据支持了以前未知的作用PPAR-alpha的行为调节，并提出了新的策略，为治疗神经精神病理学的特点是缺乏神经甾体生成，包括创伤后应激障碍和重度抑郁症。
BACKGROUND: The endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-alpha 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-alpha on emotional behavior are poorly understood.METHODS: We studied the impact of PPAR-alpha 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.RESULTS: 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-alpha synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-alpha deletion, PPAR-alpha antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-alpha, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels.CONCLUSIONS: This evidence supports a previously unknown role for PPAR-alpha in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.