Enhancement of peripheral fatty acyl ethanolamide signaling prevents stress-induced social avoidance and anxiety-like behaviors in male rats.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-05-01 Epub Date: 2023-11-07 DOI:10.1007/s00213-023-06473-w

Luca Carnevali, Margherita Barbetti, Yannick Fotio, Francesca Ferlenghi, Federica Vacondio, Marco Mor, Daniele Piomelli, Andrea Sgoifo

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Abstract

Rationale: Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure.

Objectives: In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators - which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide - on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress.

Methods: Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure.

Results: URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat CONCLUSIONS: Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

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外周脂肪酰基乙醇酰胺信号传导的增强可防止雄性大鼠应激诱导的社交回避和焦虑样行为。

理由：接触创伤事件会导致社交和焦虑相关行为的改变。新出现的证据表明，外周宿主防御过程与压力诱导的行为反应的表达有关，可能有助于减轻压力暴露的负面后果。目的：在本研究中，我们使用外周限制性FAAH抑制剂URB937来研究脂质介质的脂肪酰基乙醇酰胺（FAE）家族的作用，其中包括内源性大麻素阿那酰胺和内源性PPAR-α激动剂，油酰乙醇酰胺和棕榈酰乙醇酰胺对两种行为学不同的大鼠应激模型的行为和外周生化反应的影响。方法：雄性成年大鼠暴露于急性社交失败、心理应激模型（实验1）或捕食者气味2，5-二氢-2，4，5-三甲基噻唑啉（TMT）、先天捕食者诱发恐惧的测试（实验2），随后用URB937（1或3 mg/kg，腹膜内）或载体治疗。在暴露后24小时（实验1）或7天（实验2）进行行为分析。结果：URB937预防了社交失败应激后社交回避行为和TMT暴露后焦虑相关行为的出现。进一步的URB937给药阻断了社交失败诱导的促炎细胞因子血浆浓度的短暂升高和社交失败后24小时观察到的血浆皮质酮水平的升高结论：外周FAAH调节的脂质信号的增强通过机制防止雄性大鼠出现应激诱导的社交回避和焦虑样行为这可能涉及由应激暴露诱导的外周细胞因子释放的减弱。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.