Fotio Yannick, Mabou Tagne Alex, Jung Kwang-Mook, Piomelli Daniele
Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA.
Psychopharmacology (Berl). 2023 Apr 5. doi: 10.1007/s00213-023-06358-y.
Post-traumatic stress disorder (PTSD), a chronic debilitating condition that affects nearly 5-10% of American adults, is treated with a handful of FDA-approved drugs that provide at best symptomatic relief and exert multiple side effects. Preclinical and clinical evidence shows that inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which deactivates the endocannabinoid anandamide, exhibit anxiolytic-like properties in animal models. In the present study, we investigated the effects of two novel brain-permeable FAAH inhibitors - the compounds ARN14633 and ARN14280 - in a rat model of predator stress-induced long-term anxiety used to study PTSD.
We exposed male Sprague-Dawley rats to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a volatile constituent of fox feces, and assessed anxiety-like behaviors in the elevated plus maze (EPM) test seven days later. We measured FAAH activity using a radiometric assay and brain levels of FAAH substrates by liquid chromatography/tandem mass spectrometry.
Rats challenged with TMT developed persistent (≥ 7 days) anxiety-like symptoms in the EPM test. Intraperitoneal administration of ARN14633 or ARN14280 1 h before testing suppressed TMT-induced anxiety-like behaviors with median effective doses (ED) of 0.23 and 0.33 mg/kg, respectively. The effects were negatively correlated (ARN14663: R = 0.455; ARN14280: R = 0.655) with the inhibition of brain FAAH activity and were accompanied by increases in brain FAAH substrate levels.
The results support the hypothesis that FAAH-regulated lipid signaling serves important regulatory functions in the response to stress and confirm that FAAH inhibitors may be useful for the management of PTSD.
创伤后应激障碍（PTSD）是一种慢性衰弱性疾病，影响着近5% - 10%的美国成年人，目前使用的几种FDA批准的药物治疗效果不佳，且有多种副作用。临床前和临床证据表明，脂肪酸酰胺水解酶（FAAH）抑制剂可使内源性大麻素花生四烯乙醇胺失活，在动物模型中具有抗焦虑样特性。在本研究中，我们在用于研究PTSD的捕食者应激诱导长期焦虑大鼠模型中，研究了两种新型脑渗透性FAAH抑制剂——化合物ARN14633和ARN14280的作用。
我们将雄性Sprague-Dawley大鼠暴露于狐狸粪便的挥发性成分2,5 - 二氢 - 2,4,5 - 三甲基噻唑啉（TMT）中，并在7天后通过高架十字迷宫（EPM）试验评估焦虑样行为。我们使用放射性测定法测量FAAH活性，并通过液相色谱/串联质谱法测量FAAH底物的脑内水平。
用TMT攻击的大鼠在EPM试验中出现持续（≥7天）的焦虑样症状。在测试前1小时腹腔注射ARN14633或ARN14280可抑制TMT诱导的焦虑样行为，中位有效剂量（ED）分别为0.23和0.33mg/kg。这些作用与脑FAAH活性的抑制呈负相关（ARN14663：R = 0.455；ARN14280：R = 0.655），并伴有脑FAAH底物水平的升高。
结果支持以下假设，即FAAH调节的脂质信号在应激反应中起重要调节作用，并证实FAAH抑制剂可能对PTSD的治疗有用。
