The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants...The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants accumulated along many outbreeding generations. In the present study, 90 NIH-HS male rats were tested for anxiety/fearfulness in the elevated zero-maze and in the open-field test in order to investigate the associations among defensive responses from both tests and, in particular, those among open- field self-grooming and freezing. These associations were evaluated by means of a correlational-factorial approach and an analysis of differences between sub- groups displaying extreme scores in representative variables. The final factor analysis revealed a first factor with high loadings of all variables from the zero-maze (“Maze timidity/conflict” factor), and a second (independent) factor dominated by open-field crossings (-0.74), rearings (-0.62) and freezing (0.65), with lower loadings of open-field grooming (-0.39) and stretched attend postures, as well as of entries and time (loadings of -0.32 to -0.25) in the open sections of the zero-maze (“Open Behavior inhibition/ desinhibition” factor), suggesting that open-field self-grooming is a response associated to activity, in the present study, rather than to inhibition. Furthermore, the finding that grooming in the OF loaded negatively in a second factor supports a relationship between grooming and dearousal. Present results, thus, are in accordance with the usefulness of these tests for the purposes they are commonly employed and add new evidence supporting their concurrent validity, as indicated by the relationships observed among measures from both tests.展开更多
Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HP...Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HPAA) is identified in brain cells as a physiological byproduct of tyramine. This study hypothesizes that 4-HPAA may regulate anxiety due to its anxiolytic properties, acting as a modulator of the GABAergic system, which plays a crucial role in the pathophysiology of anxiety disorders. Our study aims to enhance the anxiolytic effects of 4-HPAA through chemical modification to improve its pharmacokinetic properties. Three derivatives, namely Isopropyl-4-hydroxy-[phenyl] acetate (IHPA), Isopropyl-4-hydroxy-[phenyl] acetate (MPAA), and 4-methoxyphenyl acetate (MPHA), have been synthesized from 4-HPAA. This assessment will use well-established animal models, specifically the Elevated Plus-Maze (EPM) and Zero Maze (EZM) tests, selected for their validity in replicating anxiety-like symptoms in animals. Chronic caffeine administration via drinking water (0.3 g/l for 14 days) was employed to induce an anxiety state for testing purposes. IHPA and MPAA demonstrated significant anxiolyticactivity when tested in the EPM and EZM experiments. Molecular docking simulations using AutoDock Vina indicated that 4-HPAA derivatives had docking scores ranging from −5.8 to −4.8 kcal/mol, compared to the standard anxiolytic medication Diazepam, which scored −7.1 kcal/mol. These scores suggest a potential for 4-HPAA derivatives to interact effectively with the Gamma-aminobutyric acid (GABA_A) receptor. In conclusion, our in vivo and in silico analyses indicate a promising anxiolytic potential for 4-HPAA derivatives.展开更多
目的探讨高架﹢迷宫实验(elevated plus maze,EPM)与高架〇迷宫实验(elevated zero maze,EZM)作为经典状态焦虑动物模型的相关性。方法昆明小鼠(4周龄,♂/♀)依次进行EPM、EZM,实验间隔1周,采用摄像系统记录5min行为变化,包括进入时间...目的探讨高架﹢迷宫实验(elevated plus maze,EPM)与高架〇迷宫实验(elevated zero maze,EZM)作为经典状态焦虑动物模型的相关性。方法昆明小鼠(4周龄,♂/♀)依次进行EPM、EZM,实验间隔1周,采用摄像系统记录5min行为变化,包括进入时间及进入次数;最终纳入实验参数有:开臂区进入时间百分率(Otime%)和两臂区进入总次数(Entries);采用描述性分析、聚类分析、因子分析、相关分析及一致性检验进行EPM与EZM行为模式、结构维度及相关性研究。结果t检验结果显示,与EPM相比,EZM Otime%(♂/♀/♂+♀)均降低,而Entries(♂/♂+♀)均升高,且差异有统计学意义;Fiedman检验结果显示,EPM/EZM实验参数Otime%(♂/♀/♂+♀)、Entries(♂/♀/♂+♀)重复测量片段间差异均有统计学意义;Wilcoxon检验结果显示,与EPM相比,EZM Otime%在1st min(♂/♀/♂+♀)、2nd min(♂/♀/♂+♀)、3rd min(♀/♂+♀)均降低,而Entries在1st min(♂/♂+♀)、4th min(♂/♀/♂+♀)、5th min(♂+♀)均升高,且差异有统计学意义。聚类分析结果显示,EPM/EZM实验参数可分组为EPM类和EZM类(♂/♀/♂+♀)。因子分析结果显示,EPM/EZM实验参数可提取为EPM因子和EZM因子(♂/♀/♂+♀)。相关分析结果显示,EPM和EZM实验参数Otime、Entries均具有一般或者较差相关性(♂/♀/♂+♀)。一致性检验结果显示,EPM和EZM实验参数Otime%(♂/♀/♂+♀)具有一般一致性。结论尽管EPM/EZM作为状态焦虑动物模型具有相类似内在原理,但是因为其外在环境(结构)差异性,导致EPM/EZM具有不同行为模式,分属不同结构维度,且仅具有一般相关性和一致性,而稳定性实验参数则首选Otime%。展开更多
基金CNPq(201456/2011-7)Supported by grants for the MICINN(PSI2009-10532),“Fundacio La Marato TV3”(ref.092630/31),2009SGR-0051the European project/consortium“EURATRANS”(grant agreement HEALTH-F4-2010-241504).
文摘The National Institutes of Health Genetically Heterogeneous Rat Stock (NIH-HS) is a unique tool for genetic studies of complex traits due to its high genetic heterogeneity and to its high level of genetic recombinants accumulated along many outbreeding generations. In the present study, 90 NIH-HS male rats were tested for anxiety/fearfulness in the elevated zero-maze and in the open-field test in order to investigate the associations among defensive responses from both tests and, in particular, those among open- field self-grooming and freezing. These associations were evaluated by means of a correlational-factorial approach and an analysis of differences between sub- groups displaying extreme scores in representative variables. The final factor analysis revealed a first factor with high loadings of all variables from the zero-maze (“Maze timidity/conflict” factor), and a second (independent) factor dominated by open-field crossings (-0.74), rearings (-0.62) and freezing (0.65), with lower loadings of open-field grooming (-0.39) and stretched attend postures, as well as of entries and time (loadings of -0.32 to -0.25) in the open sections of the zero-maze (“Open Behavior inhibition/ desinhibition” factor), suggesting that open-field self-grooming is a response associated to activity, in the present study, rather than to inhibition. Furthermore, the finding that grooming in the OF loaded negatively in a second factor supports a relationship between grooming and dearousal. Present results, thus, are in accordance with the usefulness of these tests for the purposes they are commonly employed and add new evidence supporting their concurrent validity, as indicated by the relationships observed among measures from both tests.
文摘Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HPAA) is identified in brain cells as a physiological byproduct of tyramine. This study hypothesizes that 4-HPAA may regulate anxiety due to its anxiolytic properties, acting as a modulator of the GABAergic system, which plays a crucial role in the pathophysiology of anxiety disorders. Our study aims to enhance the anxiolytic effects of 4-HPAA through chemical modification to improve its pharmacokinetic properties. Three derivatives, namely Isopropyl-4-hydroxy-[phenyl] acetate (IHPA), Isopropyl-4-hydroxy-[phenyl] acetate (MPAA), and 4-methoxyphenyl acetate (MPHA), have been synthesized from 4-HPAA. This assessment will use well-established animal models, specifically the Elevated Plus-Maze (EPM) and Zero Maze (EZM) tests, selected for their validity in replicating anxiety-like symptoms in animals. Chronic caffeine administration via drinking water (0.3 g/l for 14 days) was employed to induce an anxiety state for testing purposes. IHPA and MPAA demonstrated significant anxiolyticactivity when tested in the EPM and EZM experiments. Molecular docking simulations using AutoDock Vina indicated that 4-HPAA derivatives had docking scores ranging from −5.8 to −4.8 kcal/mol, compared to the standard anxiolytic medication Diazepam, which scored −7.1 kcal/mol. These scores suggest a potential for 4-HPAA derivatives to interact effectively with the Gamma-aminobutyric acid (GABA_A) receptor. In conclusion, our in vivo and in silico analyses indicate a promising anxiolytic potential for 4-HPAA derivatives.
