Sex-dependent changes induced by combined low-level systemic inflammation and chronic mild unpredictable stress in rats are partially attenuated by positive modulation of α5 GABAA receptors

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior Pub Date : 2025-05-14 DOI:10.1016/j.pbb.2025.174032

Jana Ivanović , Jovana Aranđelović , Kristina Jezdić , Branka Divović Matović , Ivan Jančić , Bojan Batinić , Dishary Sharmin , Prithu Mondal , James M. Cook , Miroslav M. Savić

{"title":"Sex-dependent changes induced by combined low-level systemic inflammation and chronic mild unpredictable stress in rats are partially attenuated by positive modulation of α5 GABAA receptors","authors":"Jana Ivanović , Jovana Aranđelović , Kristina Jezdić , Branka Divović Matović , Ivan Jančić , Bojan Batinić , Dishary Sharmin , Prithu Mondal , James M. Cook , Miroslav M. Savić","doi":"10.1016/j.pbb.2025.174032","DOIUrl":null,"url":null,"abstract":"<div><div>The response to prolonged mild stress is dichotomous, has been associated with depression, anxiety and cognitive impairment, and may be modulated by various factors such as sex or GABA-ergic transmission. We investigated in rats the sex-dependent effects of four doses of lipopolysaccharide (LPS) in one week, followed by four weeks of chronic unpredictable mild stress (CUMS), on behavioral parameters assessed in the weekly sucrose preference test and spontaneous locomotor activity, as well as in the behavioral battery (elevated-plus-maze test, resident-intruder test, three-chamber test and forced-swim test) conducted after 7 days of treatment with GL-II-73, a positive allosteric modulator selective for α5 GABA<sub>A</sub> receptors (LPS/CUMS-GL-II-73), or with solvent (LPS/CUMS-SOL), beginning after the third week of CUMS. At the end of stress, sucrose intake was significantly increased in LPS/CUMS-SOL compared to male controls (CRTL); in females, LPS/CUMS-GL-II-73 showed a significantly higher preference for sucrose than CTRL-SOL. In males, forced swimming time was significantly longer in LPS/CUMS-SOL compared to CTRL-SOL. Social play in the resident-intruder test was reduced in female LPS/CUMS-SOL, and GL-II-73 and GL-II-73 tended to reversed this stress effect. LPS/CUMS-GL-II-73 males showed no significant social recognition in the three-chamber test. Ex vivo tests showed an increase in <em>Gabra5</em> gene expression in the ventral hippocampus in LPS/CUMS-GL-II-73 compared to CTRL-SOL. The subtle changes in the measured parameters suggest that the clinical benefit of positive modulation of α5 GABA<sub>A</sub> receptors may result from focusing on the sex-specific niches of behavioral domains affected by prolonged stressors.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"253 ","pages":"Article 174032"},"PeriodicalIF":3.3000,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology Biochemistry and Behavior","FirstCategoryId":"102","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0091305725000796","RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

The response to prolonged mild stress is dichotomous, has been associated with depression, anxiety and cognitive impairment, and may be modulated by various factors such as sex or GABA-ergic transmission. We investigated in rats the sex-dependent effects of four doses of lipopolysaccharide (LPS) in one week, followed by four weeks of chronic unpredictable mild stress (CUMS), on behavioral parameters assessed in the weekly sucrose preference test and spontaneous locomotor activity, as well as in the behavioral battery (elevated-plus-maze test, resident-intruder test, three-chamber test and forced-swim test) conducted after 7 days of treatment with GL-II-73, a positive allosteric modulator selective for α5 GABA_A receptors (LPS/CUMS-GL-II-73), or with solvent (LPS/CUMS-SOL), beginning after the third week of CUMS. At the end of stress, sucrose intake was significantly increased in LPS/CUMS-SOL compared to male controls (CRTL); in females, LPS/CUMS-GL-II-73 showed a significantly higher preference for sucrose than CTRL-SOL. In males, forced swimming time was significantly longer in LPS/CUMS-SOL compared to CTRL-SOL. Social play in the resident-intruder test was reduced in female LPS/CUMS-SOL, and GL-II-73 and GL-II-73 tended to reversed this stress effect. LPS/CUMS-GL-II-73 males showed no significant social recognition in the three-chamber test. Ex vivo tests showed an increase in Gabra5 gene expression in the ventral hippocampus in LPS/CUMS-GL-II-73 compared to CTRL-SOL. The subtle changes in the measured parameters suggest that the clinical benefit of positive modulation of α5 GABA_A receptors may result from focusing on the sex-specific niches of behavioral domains affected by prolonged stressors.

查看原文本刊更多论文

大鼠低水平全身炎症和慢性轻度不可预测应激联合引起的性别依赖性变化可通过α5 GABAA受体的阳性调节部分减弱

对长期轻度压力的反应是两面性的，与抑郁、焦虑和认知障碍有关，并可能受到各种因素的调节，如性别或氨基丁酸能传递。我们研究了四种剂量的脂多糖（LPS）在一周内对大鼠的性别依赖性影响，随后是4周的慢性不可预测轻度应激（CUMS），对每周蔗糖偏好测试和自发运动活动中评估的行为参数，以及在用GL-II-73治疗7天后进行的行为电池（升高加迷宫测试、居住者测试、三室测试和强迫游泳测试）的影响。一种选择性α5 GABAA受体（LPS/ cms - gl - ii -73）或与溶剂（LPS/ cms - sol）的正变质调节剂，在CUMS治疗第三周后开始。应激结束时，LPS/ coms - sol组的蔗糖摄入量显著高于雄性对照组（CRTL）；在雌性中，LPS/ cams - gl - ii -73对蔗糖的偏好明显高于CTRL-SOL。在男性中，LPS/CUMS-SOL组的强迫游泳时间明显长于CTRL-SOL组。雌性LPS/ cms - sol的社会玩耍减少，而GL-II-73和GL-II-73倾向于逆转这种应激效应。LPS/ cms - gl - ii -73雄性在三室测试中没有明显的社会认知。体外实验显示，与CTRL-SOL相比，LPS/ cms - gl - ii -73小鼠腹侧海马Gabra5基因表达增加。测量参数的微妙变化表明，α5 GABAA受体的阳性调节可能是由于关注受长时间应激影响的行为域的性别特异性壁龛而产生的临床益处。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmacology Biochemistry and Behavior 医学-行为科学

CiteScore

6.40

自引率

2.80%

发文量

122

审稿时长

38 days

期刊介绍： Pharmacology Biochemistry & Behavior publishes original reports in the areas of pharmacology and biochemistry in which the primary emphasis and theoretical context are behavioral. Contributions may involve clinical, preclinical, or basic research. Purely biochemical or toxicology studies will not be published. Papers describing the behavioral effects of novel drugs in models of psychiatric, neurological and cognitive disorders, and central pain must include a positive control unless the paper is on a disease where such a drug is not available yet. Papers focusing on physiological processes (e.g., peripheral pain mechanisms, body temperature regulation, seizure activity) are not accepted as we would like to retain the focus of Pharmacology Biochemistry & Behavior on behavior and its interaction with the biochemistry and neurochemistry of the central nervous system. Papers describing the effects of plant materials are generally not considered, unless the active ingredients are studied, the extraction method is well described, the doses tested are known, and clear and definite experimental evidence on the mechanism of action of the active ingredients is provided.