Pharmacology Biochemistry and Behavior最新文献_第7页

Prenatal serotonin depletion persistently disrupts social behavior and modulates ΔFosB and SERT expression in mice 产前血清素耗竭持续破坏小鼠的社会行为并调节ΔFosB和SERT表达。

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-30 DOI: 10.1016/j.pbb.2025.174043

María Carolina Fabio , María Victoria Mujica , Elisa Fogliatti , María Victoria Aguilar , Alicia Laura Degano , Ricardo Marcos Pautassi

Embryonic fluctuations in serotonin (5-HT) levels during pregnancy have been associated with maternal depression and linked to social deficits and neuropsychiatric disorders in offspring. This preclinical study examined the long-term effects of transient prenatal 5-HT depletion on social, anxiety-like, and depressive-like behaviors across development, and evaluated associated changes in serotonergic markers and neuronal activity in key brain regions.

Pregnant C57BL/6 mice were administered the 5-HT synthesis inhibitor para-chlorophenylalanine (PCPA), or its vehicle, from gestational day 12.5 to 14.5. Maternal affect and caregiving behavior were assessed postnatally, and offspring of both sexes were evaluated for social interaction, compulsive behavior, locomotion, ultrasonic vocalizations, and helplessness during infancy, adolescence, and adulthood. Immunohistochemistry was performed in the offspring to assess serotonin transporter (SERT) and ΔFosB expression in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc).

PCPA administration did not significantly alter depressive- or anxiety-like behavior in the dams, nor did it significantly affect maternal caregiving. The offspring prenatally exposed to PCPA exhibited reduced social interaction and increased non-social behaviors compared to controls during adolescence and adulthood. Prenatal serotonin depletion also led to decreased SERT and ΔFosB expression in the mPFC and NAc, indicating disrupted serotonergic signaling and altered neuronal activity in mood- and reward-related brain regions.

The findings suggest that even brief disruptions of serotonergic signaling during gestation can induce lasting social deficits and neurobiological alterations relevant to the pathophysiology of neurodevelopmental disorders.

怀孕期间胚胎血清素（5-HT）水平的波动与母亲抑郁有关，并与后代的社交缺陷和神经精神障碍有关。这项临床前研究检查了短暂的产前5-羟色胺缺失对发育过程中社交、焦虑样和抑郁样行为的长期影响，并评估了大脑关键区域5-羟色胺能标记物和神经元活动的相关变化。妊娠C57BL/6小鼠在妊娠12.5 ~ 14.5天给予5-羟色胺合成抑制剂对氯苯丙氨酸（PCPA）或其载体。在出生后评估母亲的情感和照顾行为，并评估两性后代在婴儿期、青春期和成年期的社会互动、强迫行为、运动、超声波发声和无助感。对后代进行免疫组化，以评估血清素转运体（SERT）和ΔFosB在内侧前额叶皮层（mPFC）和伏隔核（NAc）中的表达。PCPA给药并没有显著改变母鼠的抑郁或焦虑样行为，也没有显著影响母鼠的照料。与对照组相比，产前暴露于PCPA的后代在青春期和成年期表现出较少的社会互动和增加的非社会行为。产前血清素缺失也导致mPFC和NAc中SERT和ΔFosB表达降低，表明血清素能信号被破坏，情绪和奖励相关脑区神经元活动改变。研究结果表明，即使是妊娠期血清素信号的短暂中断也会导致持久的社会缺陷和与神经发育障碍病理生理学相关的神经生物学改变。

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引用次数: 0

Population-dependent impacts of para-chlorophenylalanine, a tryptophan hydroxylase inhibitor, on homebase formation and thigmotaxis in adult zebrafish 对氯苯丙氨酸（一种色氨酸羟化酶抑制剂）对成年斑马鱼母碱形成和吸氧性的种群依赖性影响

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-26 DOI: 10.1016/j.pbb.2025.174042

Cássio M. Resmim , João V. Borba , Rossano M. Silva , Hevelyn S. Moraes , Camilla W. Pretzel , Julia Canzian , Barbara D. Fontana , Maribel A. Rubin , Eduardo P. Rico , Matthew O. Parker , Denis B. Rosemberg

Alterations in monoamine levels, such as serotonin, play a role in the pathophysiology of affective disorders. Para-chlorophenylalanine (pCPA), a tryptophan hydroxylase inhibitor, impairs serotonin synthesis and increases anxiety-like behaviors in various species. Outbred zebrafish population, such as short fin (SF) and leopard (LEO), differ in serotonin expression, habituation patterns, and responses to novel environments. Locomotor and exploratory profiles are strongly influenced by homebase behavior, which can be assessed in the open field test (OFT). To further investigate a putative role of the serotoninergic system in homebase formation and exploratory behavior dynamics, we administered pCPA to two zebrafish populations (SF and LEO) with distinct anxiety profiles and homebase occupancy. Fish received intraperitoneal injections of pCPA (300 mg/kg) or vehicle for two consecutive days, followed by a 30-min OFT 24 h later. Both pCPA-treated populations showed increased locomotion and periphery occupancy was elevated during the habituation period (first 15 min of testing). Although pCPA did not alter homebase-related behaviors in LEO, the SF population exhibited a delayed homebase formation, likely due to disrupted exploratory-related mechanisms. Furthermore, Principal Component Analysis (PCA) and K-means clustering revealed that behaviors related to periphery occupancy and distance traveled accounted for approximately 80 % of the observed data variability. Collectively, our data show that pCPA impairs homebase formation, with stronger effects in SF fish and increases thigmotaxis. Overall, these results suggest that pCPA disrupts the organization of exploratory behavior, particularly the habituation processes, probably associated with anxiety-like phenotypes.

单胺水平的改变，如血清素，在情感性障碍的病理生理中起作用。对氯苯丙氨酸（pCPA）是一种色氨酸羟化酶抑制剂，在各种物种中损害血清素合成并增加焦虑样行为。近亲繁殖的斑马鱼种群，如短鳍（SF）和豹纹（LEO），在血清素表达、适应模式和对新环境的反应方面存在差异。本垒行为对运动和探索剖面有很大影响，这可以在野外测试（OFT）中进行评估。为了进一步研究血清素能系统在本垒形成和探索性行为动力学中的作用，我们对两个具有不同焦虑特征和本垒占用的斑马鱼种群（SF和LEO）进行了pCPA治疗。鱼连续两天腹腔注射pCPA （300 mg/kg）或载体，24小时后进行30分钟的OFT。在习惯化期间（测试的前15分钟），两个pppa处理的种群都表现出运动增加和外围占用率升高。尽管pCPA没有改变LEO中与本垒相关的行为，但SF群体表现出本垒形成的延迟，可能是由于探索相关机制的破坏。此外，主成分分析（PCA）和K-means聚类表明，与周边占用和行驶距离相关的行为约占观察到的数据变异性的80%。总的来说，我们的数据表明，pCPA损害了本垒的形成，对SF鱼的影响更大，并增加了移植物性。总的来说，这些结果表明，pCPA破坏了探索行为的组织，特别是习惯化过程，可能与焦虑样表型有关。

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引用次数: 0

Administration of paroxetine during pregnancy affects behavioral changes and hippocampal cell proliferation in male offspring in rats 妊娠期给予帕罗西汀影响雄性后代大鼠行为改变和海马细胞增殖

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-26 DOI: 10.1016/j.pbb.2025.174041

Junko Horie , Tomoya Kinjo , Masanobu Ito , Toshihito Suzuki

Background

Although the use of antidepressants during pregnancy has increased over the last several decades, their safety has remained a topic of debate. Selective serotonin reuptake inhibitors (SSRIs) can cross the placenta and affect perinatal outcomes in infants exposed during pregnancy. Recent studies suggest new risks for not only for structural malformations, but also long-term behavioral, developmental, and emotional disorders in offspring.

Aim

We aimed to elucidate the effects by which in utero paroxetine exposure may affect the behavior and hippocampus of the offspring of paroxetine-treated rodent mothers.

Methods

Paroxetine was administered daily to pregnant female Wistar rats from embryonic day (ED) 12.5 to ED 21 with oral sondes. Paroxetine 1 mg/kg/day or paroxetine 2.5 mg/kg/day or saline was given to the control group. We evaluated spontaneous locomotor activity, spontaneous alternation behavior using the Y-maze test, and anxiety behavior using the elevated plus maze (EPM) in male offspring at postnatal day 30. Bromodeoxyuridine (BrdU)-positive cells in the hippocampus were counted using a fluorescence microscope.

Results

Locomotor activities significantly increased in the paroxetine 2.5 mg compared with the control group. The paroxetine 2.5 mg group spent less time in the closed arm than did the control and paroxetine 1 mg groups in the EPM. The number of BrdU-positive cells in the dentate gyrus was significantly increased in the paroxetine 2.5 mg compared with the control group.

Conclusions

These findings suggest that oral administration of paroxetine during pregnancy induces hyperactivity, decreases anxiety, and increases cell proliferation in the hippocampus of male offspring.

虽然在过去的几十年里，怀孕期间使用抗抑郁药的情况有所增加，但它们的安全性仍然是一个有争议的话题。选择性5 -羟色胺再摄取抑制剂（SSRIs）可以穿过胎盘并影响怀孕期间暴露的婴儿围产期结局。最近的研究表明，新的风险不仅是结构畸形，而且还包括后代的长期行为、发育和情绪障碍。目的：我们旨在阐明子宫内暴露于帕罗西汀可能影响帕罗西汀治疗的啮齿动物母亲后代的行为和海马的影响。方法妊娠雌性Wistar大鼠从胚胎期12.5 ~ 21天每天口服帕罗西汀。对照组给予帕罗西汀1 mg/kg/day或帕罗西汀2.5 mg/kg/day或生理盐水。在出生后第30天，我们用y迷宫测试评估了雄性后代的自发运动活动、自发交替行为，用升高正迷宫（EPM）评估了焦虑行为。荧光显微镜下计数海马中溴脱氧尿苷（BrdU）阳性细胞。结果与对照组相比，帕罗西汀2.5 mg组心肌运动活性明显增强。与对照组和帕罗西汀1 mg组相比，帕罗西汀2.5 mg组在EPM中的封闭臂时间更短。与对照组相比，paroxetine 2.5 mg组齿状回brdu阳性细胞数量明显增加。结论妊娠期口服帕罗西汀可诱导雄性后代多动、减轻焦虑、增加海马细胞增殖。

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引用次数: 0

Enhanced novelty-seeking after early adolescent exposure to vicarious social defeat predicts the vulnerability of female mice to cocaine reward 在青春期早期暴露于替代性的社会失败后，寻求新奇事物的增强预示着雌性老鼠对可卡因奖励的脆弱性。

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-23 DOI: 10.1016/j.pbb.2025.174039

María Ángeles Martínez-Caballero , Claudia Calpe-López , María Pilar García-Pardo , María Carmen Arenas , Jose Enrique de la Rubia Ortí , María Benlloch , Carmen Manzanedo , María Asunción Aguilar

Stressful experiences can have a serious impact on adolescents, as the process of brain maturation, particularly of the prefrontal cortex, takes place during this developmental period. In animal models, male mice exposed to social defeat during early or late adolescence show increased vulnerability to cocaine reward, but this effect has only been studied in late adolescent female mice exposed to Vicarious Intermittent Social Defeat (VISD). The aim of the present study was to investigate the biochemical and behavioural effects of exposure to VISD during early adolescence in female mice. VISD only induced anxiety-like symptoms in the elevated plus maze (EPM) and increased novelty-seeking behaviour in the hole-board test. Furthermore, the behavioural profile of VISD-exposed mice in these tests was associated with their vulnerability or resilience to cocaine reward in adulthood. Female mice that exhibited a higher frequency of entries in the closed arms of the EPM and a lower latency of dips in the hole-board subsequently acquired cocaine-induced conditioned place preference. Thus, exposure of female mice to VISD during early adolescence also induced short-term changes that increased sensitivity to cocaine reward in susceptible individuals.

压力经历会对青少年产生严重影响，因为大脑成熟的过程，特别是前额皮质，发生在这个发育时期。在动物模型中，在青春期早期或晚期暴露于社交失败的雄性小鼠对可卡因奖励的脆弱性增加，但这种影响仅在青春期晚期暴露于替代性间歇性社交失败（VISD）的雌性小鼠中进行了研究。本研究的目的是研究雌性小鼠青春期早期暴露于VISD的生化和行为影响。VISD仅在升高+迷宫（EPM）中引起焦虑样症状，并在孔板测试中增加寻求新奇的行为。此外，在这些测试中，暴露于visd的小鼠的行为特征与它们成年后对可卡因奖励的脆弱性或恢复力有关。雌性小鼠进入EPM闭合臂的频率较高，在孔板上的潜伏期较低，随后获得了可卡因诱导的条件位置偏好。因此，雌性小鼠在青春期早期暴露于VISD也会引起短期变化，增加易感个体对可卡因奖励的敏感性。

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引用次数: 0

Pharmacological and genetic manipulation of glyoxalase-1 (GLO1) does not alter locomotor responses or conditioned place preference induced by cocaine or oxycodone. 乙二醛酶-1 （GLO1）的药理学和遗传学操作不会改变可卡因或羟考酮诱导的运动反应或条件位置偏好。

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-22 DOI: 10.1016/j.pbb.2025.174040

Elizabeth Alcantara , Michelle R. Doyle , Clara A. Ortez , Anne Ilustrisimo , Bloom Stromberg , Amanda M. Barkley-Levenson , Abraham A. Palmer

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABA_A receptors. MG is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption. The goal of these studies was to determine whether manipulation of GLO1 could alter cocaine- or oxycodone-induced locomotor activation and/or conditioned place preference (CPP) to cocaine or oxycodone. We used both pharmacological and genetic manipulations of GLO1 to address this question. Administration of the GLO1 inhibitor s-bromobenzylglutathione cyclopentyl diester (pBBG) did not alter the locomotor response to cocaine or oxycodone. Additionally, pBBG had no significant effect on place preference for cocaine or oxycodone. Genetic knockdown of Glo1, which is conceptually similar to pharmacological inhibition, did not have any significant effects on CPP to cocaine. Finally, Glo1 overexpression did not affect locomotor response to cocaine. In summary, our results did not show any effect of pharmacological or genetic manipulations of GLO1 on the locomotor response or CPP to either cocaine or oxycodone.

甲基乙二醛（MG）是糖酵解的内源性非酶副产物，作为GABAA受体的部分激动剂。MG由乙二醛酶-1 （GLO1）代谢。抑制GLO1增加甲基乙二醛水平，并已被证明可以调节多种行为，包括减少寻求可卡因配对线索和乙醇消耗。这些研究的目的是确定GLO1的操纵是否可以改变可卡因或羟考酮诱导的运动激活和/或对可卡因或羟考酮的条件性位置偏好（CPP）。我们使用GLO1的药理学和遗传学操作来解决这个问题。GLO1抑制剂s-溴苄基谷胱甘肽环戊二酯（pBBG）的使用没有改变对可卡因或羟考酮的运动反应。此外，pBBG对可卡因或羟考酮的位置偏好没有显著影响。基因敲除Glo1在概念上类似于药物抑制，对可卡因的CPP没有任何显著影响。最后，Glo1过表达不影响对可卡因的运动反应。总之，我们的结果没有显示GLO1的药理学或遗传操作对可卡因或羟考酮的运动反应或CPP有任何影响。

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引用次数: 0

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 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

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

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.

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。

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引用次数: 0

Reward contamination in restrictive anorexia nervosa: A meta-analysis of functional MRI studies 限制性神经性厌食症的奖励污染：功能性MRI研究的荟萃分析

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-08 DOI: 10.1016/j.pbb.2025.174031

Charlotte S. Rye , Felippe E. Amorim , Laetitia H.E. Ward , Amy L. Milton

Individuals with anorexia nervosa (AN) are typically anhedonic, leading to the suggestion that intrinsic disturbances of reward processing may represent a trait marker of the disorder. Previous studies have used task-based functional magnetic resonance imaging (fMRI) to investigate reward-related brain activity in AN and reported altered activation in the prefrontal cortex, dorsal posterior cingulate cortex, and rostral anterior cingulate cortex. However, likely due to the varied paradigms and methodologies used, as well as the heterogeneity in sample characteristics, results have proved inconsistent. To determine whether AN patients with the restrictive subtype (AN-r) show different reward-induced activation patterns to matched healthy controls (HCs) at different illness stages, we conducted a meta-analysis of 19 task-based fMRI studies of reward-processing. Using the seed-based differential mapping (SDM) technique, we found differences in reward-related brain activity between AN-r and HCs. Moreover, different brain regions showed differential activation across illness stages, with the direction and magnitude of effects dependent on specific task stimuli. These findings suggest that those with AN-r show distorted reward processing as a consequence of reward contamination and alterations in valence assignment to reward stimuli. In weight-recovered AN-r patients, differences to HCs persisted but were limited to regions known to exhibit significant atrophy in AN-r, indicating that altered reward processing is associated with anorectic undernutrition. These findings have implications for developing pharmacological treatments to aid psychological recovery in AN-r.

神经性厌食症（AN）的个体是典型的快乐缺乏症，导致奖励处理的内在干扰可能是该疾病的特征标记。先前的研究使用基于任务的功能性磁共振成像（fMRI）来研究AN中与奖励相关的大脑活动，并报道了前额叶皮层、后扣带皮层背侧和前扣带皮层吻侧的激活改变。然而，可能由于所使用的范式和方法的不同，以及样本特征的异质性，结果被证明是不一致的。为了确定AN限制性亚型（AN-r）患者在不同疾病阶段是否表现出与匹配健康对照（hc）不同的奖励诱导激活模式，我们对19项基于任务的fMRI奖励处理研究进行了荟萃分析。使用基于种子的差分映射（SDM）技术，我们发现AN-r和hc之间奖赏相关的大脑活动存在差异。此外，不同的大脑区域在不同的疾病阶段表现出不同的激活，其作用的方向和大小取决于特定的任务刺激。这些发现表明，AN-r患者表现出扭曲的奖励加工，这是奖励污染和对奖励刺激的效价分配改变的结果。在体重恢复的AN-r患者中，hcc的差异持续存在，但仅限于已知AN-r显着萎缩的区域，这表明奖赏加工的改变与厌食性营养不良有关。这些发现对开发药物治疗来帮助AN-r患者的心理恢复具有启示意义。

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引用次数: 0

Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats 产后丙酸暴露破坏大鼠海马agmatine稳态，导致自闭症谱系障碍样表型的社会缺陷和认知障碍

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-01 DOI: 10.1016/j.pbb.2025.174030

Manasi Tadas , Nitu Wankhede , Pranali Chandurkar , Nandkishor Kotagale , Milind Umekar , Raj Katariya , Akash Waghade , Dadasaheb Kokare , Brijesh Taksande

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by a range of symptoms including impaired social interaction and cognitive deficits. Although the exact pathogenesis of ASD is not well established, recent clinical findings suggest a decline in levels of biogenic amine agmatine in autistic patients. The present study was designed to investigate the impact of postnatal propionic acid (PPA) exposure on hippocampal agmatine homeostasis in male rat pups and to explore a new therapeutic intervention for ASD using agmatine as a biological target. PPA is commonly used in experimental models of ASD due to its ability to induce social deficits, cognitive impairments, and stereotyped behaviors, which closely resemble key characteristics of ASD. Male rat pups were administered with PPA via the intrahippocampal route bilaterally (25 μg/0.25 μl per side) on PND-21 to simulate the ASD phenotype, and its subsequent effect on the endogenous agmatinergic system. The influence of agmatine treatment and its endogenous modulation on ASD-like phenotypes was also investigated. Behavioral assessments revealed that PPA exposure reduced sociability and social preference, caused learning and memory impairment in the Morris water maze, increased anxiety-like behavior in the elevated plus maze, and reduced exploratory behavior in the hole board test. Neurochemical analyses showed a decrease in agmatine concentration and an increase in its degrading enzyme agmatinase in the hippocampus. PPA treatment altered the content of GABA, glutamate, TNF-α, IL-6, BDNF, and also resulted in increased astrogliosis and neurotoxicity within the hippocampus. Chronic agmatine treatment and its endogenous modulation ameliorated the behavioral and biochemical disruptions induced by PPA exposure. This study highlights the critical role of hippocampal agmatinergic pathway in the etiopathogenesis of ASD, positioning agmatine as a promising therapeutic target for its treatment.

自闭症谱系障碍（ASD）是一种复杂的神经发育疾病，其特征是一系列症状，包括社交障碍和认知缺陷。虽然ASD的确切发病机制尚不清楚，但最近的临床研究结果表明，自闭症患者体内的生物源胺胍水平下降。本研究旨在探讨出生后丙酸（PPA）暴露对雄性大鼠幼鼠海马agmatine稳态的影响，并探索以agmatine为生物学靶点的ASD治疗干预新方法。PPA通常用于ASD的实验模型，因为它能够诱导社会缺陷、认知障碍和刻板行为，这些与ASD的关键特征非常相似。通过PND-21双侧海马内通路给药PPA（每侧25 μg/0.25 μl），模拟ASD表型及其对内源性agmatinergic系统的影响。还研究了胍丁氨酸处理及其内源调控对asd样表型的影响。行为评估显示，PPA暴露降低了社交能力和社会偏好，导致Morris水迷宫的学习和记忆障碍，升高+迷宫的焦虑样行为增加，孔板测试的探索行为减少。神经化学分析显示，海马体内的agmatinase浓度下降，其降解酶agmatinase增加。PPA处理改变了GABA、谷氨酸、TNF-α、IL-6、BDNF的含量，还导致海马内星形胶质细胞增生和神经毒性增加。慢性胍丁氨酸治疗及其内源性调节改善了PPA暴露引起的行为和生化破坏。本研究强调了海马agmatinergine通路在ASD发病机制中的关键作用，将agmatine定位为ASD治疗的有希望的治疗靶点。

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引用次数: 0

Crisugabalin, a ligand for the α2δ subunit of voltage-gated calcium channels, exhibits no obvious abuse potential in rodents Crisugabalin是电压门控钙通道α2δ亚基的配体，在啮齿类动物中没有明显的滥用潜力

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-05-01 DOI: 10.1016/j.pbb.2025.174015

Xiaoli Gou , Yijiang Liu , Qidi Ye , Lingzhi He , Ying Chen , Yansheng Dong , Qingyuan Meng , Zongjun Shi , Yao Li , Yao Lu , Ju Wang , Linggao Zeng

Crisugabalin, a novel third-generation ligand targeting the α2δ subunit of voltage-gated calcium channels, has been approved in China for the treatment of pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Existing research suggests that ligands for the α2δ subunit of voltage-gated calcium channels may carry a risk of abuse. To evaluate the abuse potential of crisugabalin, five well-recognized animal models were utilized in these preclinical studies. Firstly, an intravenous self-administration paradigm was implemented in rats that were self-administering propofol to assess the reinforcing effects of crisugabalin. Secondly, a rat drug discrimination study was employed to determine the pharmacological similarity between crisugabalin and the training drug midazolam. Then, a conditioned place preference (CPP) paradigm in rats was utilized to evaluate the rewarding properties of crisugabalin. After that, a spontaneous withdrawal study was conducted in rats chronically treated with crisugabalin to examine the liability of developing physical dependence. Finally, a mouse pentylenetetrazol-induced convulsion model was used following chronic exposure to crisugabalin to assess its potential for physical dependence. The results indicated that crisugabalin showed no positive reinforcing effects and did not display midazolam-like discriminative stimulus effects. Moreover, crisugabalin did not induce significant CPP in rats and there was no risk of physical dependence in the pentylenetetrazol-induced convulsion model. In the rat spontaneous withdrawal study, crisugabalin demonstrated a very low level of physical dependence. These findings suggest that crisugabalin has minimal to no potential for abuse, thereby establishing itself as a safer option relative to pregabalin and mirogabalin.

Crisugabalin是一种新型的第三代配体，靶向电压门控钙通道α2δ亚基，已在中国获批用于治疗糖尿病周围神经病变和带状疱疹后神经痛。现有研究表明，电压门控钙通道α2δ亚基配体可能存在滥用风险。为了评估crisugabalin的滥用潜力，在这些临床前研究中使用了五种公认的动物模型。首先，在自我给药异丙酚的大鼠中实施静脉自我给药范式，以评估crisugabalin的强化作用。其次，采用大鼠药物鉴别研究，确定crisugabalin与训练药物咪达唑仑的药理学相似性。然后，采用大鼠条件位置偏好（CPP）范式评价crisugabalin的奖励特性。在此之后，对长期使用crisugabalin的大鼠进行了自发戒断研究，以检查发生身体依赖的责任。最后，使用慢性暴露于crisugabalin后的小鼠戊四唑诱导惊厥模型来评估其身体依赖的可能性。结果表明，crisugabalin无正向强化作用，不表现出类似咪达唑仑的区别刺激作用。此外，crisugabalin未引起大鼠明显的CPP，并且在戊四唑诱导的惊厥模型中没有身体依赖的风险。在大鼠自发戒断研究中，crisugabalin表现出非常低的身体依赖性。这些发现表明，crisugabalin几乎没有滥用的可能性，因此相对于普瑞巴林和米罗巴林，它是一种更安全的选择。

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引用次数: 0

Prenatal maternal stress induces increased avoidance behavior in adolescent mice offspring 产前母性压力诱导青春期小鼠后代的回避行为增加

IF 3.3 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-04-30 DOI: 10.1016/j.pbb.2025.174029

Xueyong Yin , Rui Jiang , Xiaoyu Liu , Yiran Liu , Xiao Liu , Fei Zhou , Xi Yu , Shu Yan , Yunluo Li , Yuru Du , Youdong Li , Kaoqi Lian , Ye Zhao , Haishui Shi

Defensive behavior is an instinctive response to potential or actual threats, crucial for the survival and reproduction of species. It is influenced by both genetic and environmental factors and undergoes continuous changes throughout an individual's development. Stress, as a significant environmental factor, has a profound and enduring impact on reshaping an individual's behavior, particularly when experienced during early life. However, the effects of early life stress on defensive behavior remain unclear. In this study, defensive behaviors were evaluated in adolescent mice offspring exposed to prenatal stress. Serum corticosterone and neural dendritic spine density were measured. Behaviors results showed that prenatal stress significantly increased anxiety-like and avoidance behaviors in male offspring mice. Enzyme-linked immunosorbent assay (ELISA) results indicated that prenatal stress led to a significant increase in serum corticosterone levels in male offspring following predator odor exposure. Golgi staining analysis revealed a decrease in neural dendritic spine density in the medial prefrontal cortex (mPFC) of offspring. These findings suggest that behavioral changes in offspring mice caused by prenatal stress may be related to alterations in corticosterone levels and neuronal structure. However, the causation and specific mechanisms require further investigation.

防御行为是对潜在或实际威胁的本能反应，对物种的生存和繁殖至关重要。它受到遗传和环境因素的影响，并在个体的发展过程中不断变化。压力，作为一个重要的环境因素，对重塑一个人的行为有着深远而持久的影响，尤其是在生命早期经历的时候。然而，早期生活压力对防御行为的影响尚不清楚。本研究评估了暴露于产前压力下的青春期小鼠后代的防御行为。测定血清皮质酮和神经树突棘密度。行为学结果显示，产前应激显著增加雄性子代小鼠的焦虑样行为和回避行为。酶联免疫吸附试验（ELISA）结果表明，产前应激导致雄性后代在捕食者气味暴露后血清皮质酮水平显著升高。高尔基染色分析显示后代内侧前额叶皮层（mPFC）神经树突棘密度降低。这些发现表明，由产前压力引起的后代小鼠的行为改变可能与皮质酮水平和神经元结构的改变有关。然而，其原因和具体机制有待进一步研究。

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引用次数: 0