Pub Date : 2025-08-01Epub Date: 2025-05-23DOI: 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.
{"title":"Enhanced novelty-seeking after early adolescent exposure to vicarious social defeat predicts the vulnerability of female mice to cocaine reward","authors":"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","doi":"10.1016/j.pbb.2025.174039","DOIUrl":"10.1016/j.pbb.2025.174039","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"253 ","pages":"Article 174039"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01Epub Date: 2025-05-14DOI: 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 GABAA 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 GABAA 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。
{"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":"10.1016/j.pbb.2025.174032","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":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144068453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01Epub Date: 2025-05-30DOI: 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.
{"title":"Prenatal serotonin depletion persistently disrupts social behavior and modulates ΔFosB and SERT expression in mice","authors":"María Carolina Fabio , María Victoria Mujica , Elisa Fogliatti , María Victoria Aguilar , Alicia Laura Degano , Ricardo Marcos Pautassi","doi":"10.1016/j.pbb.2025.174043","DOIUrl":"10.1016/j.pbb.2025.174043","url":null,"abstract":"<div><div>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.</div><div>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).</div><div>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.</div><div>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.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"253 ","pages":"Article 174043"},"PeriodicalIF":3.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-03-05DOI: 10.1016/j.pbb.2025.173987
Xue-Ying Yang , Hui-Qin Wang , Meng-Zhang , Ai-Ping Chen , Xin-Mu Li , Zan Xing , Hong Jiang , Xu Yan , Shi-Feng Chu , Zhen-Zhen Wang , Nai-Hong Chen
Connexin 43 (Cx43) is highly expressed in astrocytes and forms gap junctions that maintain intercellular communication. Dysfunctional gap junctions in astrocytes exacerbate depressive symptoms, which has been implicated in the pathogenesis of depression. Inflammatory responses occur in the brains of most people with depression. However, it is unclear whether dysfunctional astrocyte gap junctions mediate the onset of the inflammatory response in the brains of depressed patients. Transporter protein (TSPO), the most common neuroinflammatory marker and a novel target of antidepressants identified in recent years, is mainly expressed by glial cells in the brain and is abnormally upregulated during inflammatory activation. We found that in a mouse model of chronic unpredictable stress (CUS), astrocyte gap junctions in the prefrontal cortex are impaired and the JAK2-STAT3 signaling pathway is activated, leading to an increase in the inflammatory marker TSPO. Based on this finding, we further verified using Cx43 transgenic mice that conditional knockdown of Cx43 in prefrontal cortex astrocytes also activated the JAK2-STAT3 inflammatory signaling pathway, with concomitant elevated levels of the inflammatory marker TSPO, and the mice developed depressive-like behavior. In contrast, impaired corticosterone (CORT)-induced gap junction function and increased TSPO were ameliorated by the JAK2-STAT3 inhibitor protosappanin A (PTA). Thus, targeting astrocyte Cx43 attenuates the inflammatory response in depression and improves depressive symptoms. This provides a new perspective on the pathogenesis of depression and a new therapeutic target for antidepressant research.
{"title":"Astrocyte gap junction dysfunction activates JAK2-STAT3 pathway to mediate inflammation in depression","authors":"Xue-Ying Yang , Hui-Qin Wang , Meng-Zhang , Ai-Ping Chen , Xin-Mu Li , Zan Xing , Hong Jiang , Xu Yan , Shi-Feng Chu , Zhen-Zhen Wang , Nai-Hong Chen","doi":"10.1016/j.pbb.2025.173987","DOIUrl":"10.1016/j.pbb.2025.173987","url":null,"abstract":"<div><div>Connexin 43 (Cx43) is highly expressed in astrocytes and forms gap junctions that maintain intercellular communication. Dysfunctional gap junctions in astrocytes exacerbate depressive symptoms, which has been implicated in the pathogenesis of depression. Inflammatory responses occur in the brains of most people with depression. However, it is unclear whether dysfunctional astrocyte gap junctions mediate the onset of the inflammatory response in the brains of depressed patients. Transporter protein (TSPO), the most common neuroinflammatory marker and a novel target of antidepressants identified in recent years, is mainly expressed by glial cells in the brain and is abnormally upregulated during inflammatory activation. We found that in a mouse model of chronic unpredictable stress (CUS), astrocyte gap junctions in the prefrontal cortex are impaired and the JAK2-STAT3 signaling pathway is activated, leading to an increase in the inflammatory marker TSPO. Based on this finding, we further verified using Cx43 transgenic mice that conditional knockdown of Cx43 in prefrontal cortex astrocytes also activated the JAK2-STAT3 inflammatory signaling pathway, with concomitant elevated levels of the inflammatory marker TSPO, and the mice developed depressive-like behavior. In contrast, impaired corticosterone (CORT)-induced gap junction function and increased TSPO were ameliorated by the JAK2-STAT3 inhibitor protosappanin A (PTA). Thus, targeting astrocyte Cx43 attenuates the inflammatory response in depression and improves depressive symptoms. This provides a new perspective on the pathogenesis of depression and a new therapeutic target for antidepressant research.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 173987"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Postnatal propionic acid exposure disrupts hippocampal agmatine homeostasis leading to social deficits and cognitive impairment in autism spectrum disorder-like phenotype in rats","authors":"Manasi Tadas , Nitu Wankhede , Pranali Chandurkar , Nandkishor Kotagale , Milind Umekar , Raj Katariya , Akash Waghade , Dadasaheb Kokare , Brijesh Taksande","doi":"10.1016/j.pbb.2025.174030","DOIUrl":"10.1016/j.pbb.2025.174030","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174030"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-29DOI: 10.1016/j.pbb.2025.174026
Huan Zhang , Wen Si , Bo Wang , Jiao Han , Fan Ding , Qingsheng Xue , Xiaohua Cao
While N-methyl-d-aspartate receptor (NMDAR) hypofunction has been suggested as a hallmark of schizophrenia, the role of subunit-specific dysregulation such as GluN2A overexpression remains poorly understood. The present study comprehensively investigated the impact of GluN2A overexpression on behavioral phenotypes, cognitive functions, and synaptic plasticity in transgenic mice with forebrain-specific overexpression of the GluN2A subunit (GluN2A-TG). Behavioral assessments revealed schizophrenia-like phenotypes, including prolonged stereotypic movement duration, impaired sensorimotor gating, reduced social interaction, and diminished nest-building activity in GluN2A-TG mice. Consistently, GluN2A-TG mice exhibited not only deficits in spatial working memory and olfactory working memory but also impaired associative learning. In addition, both long-term potentiation and long-term depression were significantly attenuated in the prefrontal cortex (PFC) of GluN2A-TG mice. Furthermore, electrophysiological analysis of NMDAR-mediated excitatory postsynaptic currents in PFC neurons revealed altered kinetics characterized by a faster decay time and significantly increased amplitude in GluN2A-TG mice. Collectively, these findings suggest that GluN2A overexpression may induce schizophrenia-like phenotypes via impairing NMDAR-dependent long-term synaptic plasticity in the PFC, likely due to altered NMDAR subunit composition leading to disrupted calcium signaling dynamics. These results provide critical insights into the pathological role of GluN2A in schizophrenia.
{"title":"Schizophrenia-like phenotypes and long-term synaptic plasticity impairment in GluN2A-transgenic mice","authors":"Huan Zhang , Wen Si , Bo Wang , Jiao Han , Fan Ding , Qingsheng Xue , Xiaohua Cao","doi":"10.1016/j.pbb.2025.174026","DOIUrl":"10.1016/j.pbb.2025.174026","url":null,"abstract":"<div><div>While <em>N</em>-methyl-<span>d</span>-aspartate receptor (NMDAR) hypofunction has been suggested as a hallmark of schizophrenia, the role of subunit-specific dysregulation such as GluN2A overexpression remains poorly understood. The present study comprehensively investigated the impact of GluN2A overexpression on behavioral phenotypes, cognitive functions, and synaptic plasticity in transgenic mice with forebrain-specific overexpression of the GluN2A subunit (GluN2A-TG). Behavioral assessments revealed schizophrenia-like phenotypes, including prolonged stereotypic movement duration, impaired sensorimotor gating, reduced social interaction, and diminished nest-building activity in GluN2A-TG mice. Consistently, GluN2A-TG mice exhibited not only deficits in spatial working memory and olfactory working memory but also impaired associative learning. In addition, both long-term potentiation and long-term depression were significantly attenuated in the prefrontal cortex (PFC) of GluN2A-TG mice. Furthermore, electrophysiological analysis of NMDAR-mediated excitatory postsynaptic currents in PFC neurons revealed altered kinetics characterized by a faster decay time and significantly increased amplitude in GluN2A-TG mice. Collectively, these findings suggest that GluN2A overexpression may induce schizophrenia-like phenotypes via impairing NMDAR-dependent long-term synaptic plasticity in the PFC, likely due to altered NMDAR subunit composition leading to disrupted calcium signaling dynamics. These results provide critical insights into the pathological role of GluN2A in schizophrenia.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174026"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-05-01DOI: 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.
{"title":"Crisugabalin, a ligand for the α2δ subunit of voltage-gated calcium channels, exhibits no obvious abuse potential in rodents","authors":"Xiaoli Gou , Yijiang Liu , Qidi Ye , Lingzhi He , Ying Chen , Yansheng Dong , Qingyuan Meng , Zongjun Shi , Yao Li , Yao Lu , Ju Wang , Linggao Zeng","doi":"10.1016/j.pbb.2025.174015","DOIUrl":"10.1016/j.pbb.2025.174015","url":null,"abstract":"<div><div>Crisugabalin, a novel third-generation ligand targeting the <em>α2δ</em> 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 <em>α2δ</em> 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.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174015"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-30DOI: 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.
{"title":"Prenatal maternal stress induces increased avoidance behavior in adolescent mice offspring","authors":"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","doi":"10.1016/j.pbb.2025.174029","DOIUrl":"10.1016/j.pbb.2025.174029","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174029"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-17DOI: 10.1016/j.pbb.2025.174013
Negar G. Ardabili, Shira Tan, Anthony L. Riley
Previous research has reported that pre-exposure to a variety of drugs of abuse can impact (reduce) the aversive effects of themselves and other abused compounds, often as a function of their shared pharmacological activity. In this context, the present series of studies investigated the effects of history with the synthetic cathinone eutylone on the aversive effects of cocaine, MDMA, and itself in adult, male Sprague-Dawley rats. Given eutylone's structural similarities with its parent compound methylone, it was predicted that its ability to attenuate cocaine- and MDMA-induced taste avoidance would parallel the effects of methylone pre-exposure in this design (cocaine > MDMA). In Experiment 1, male Sprague-Dawley rats were exposed to eutylone (20 mg/kg, IP) or equivolume saline every other day for five exposures followed by taste avoidance conditioning with 20 mg/kg cocaine (SC) or 1.8 mg/kg MDMA (SC). Both cocaine and MDMA induced significant taste avoidance that developed over repeated conditioning trials. Cocaine and MDMA-induced avoidance were unaffected by eutylone history. To assess the general ability of eutylone pre-exposure to attenuate taste avoidance conditioning in the pre-exposure design, in Experiment 2, an additional set of male Sprague-Dawley rats was injected with 20 mg/kg eutylone (IP) prior to taste avoidance conditioning with eutylone (20 mg/kg (IP). Under these conditions, eutylone-induced avoidance was attenuated by eutylone pre-exposure. Given that eutylone history attenuated eutylone-induced avoidance argues that the failure to affect cocaine or MDMA was not a function of eutylone in this preparation. The inability of eutylone to attenuate the aversive effects of cocaine and MDMA despite sharing pharmacological activity suggests that eutylone's hybrid pharmacology may create a unique interoceptive effect different than that produced by either drug.
{"title":"Pre-exposure to eutylone attenuates its own aversive effects but has no impact on cocaine or MDMA: A possible role of eutylone's hybrid pharmacology","authors":"Negar G. Ardabili, Shira Tan, Anthony L. Riley","doi":"10.1016/j.pbb.2025.174013","DOIUrl":"10.1016/j.pbb.2025.174013","url":null,"abstract":"<div><div>Previous research has reported that pre-exposure to a variety of drugs of abuse can impact (reduce) the aversive effects of themselves and other abused compounds, often as a function of their shared pharmacological activity. In this context, the present series of studies investigated the effects of history with the synthetic cathinone eutylone on the aversive effects of cocaine, MDMA, and itself in adult, male Sprague-Dawley rats. Given eutylone's structural similarities with its parent compound methylone, it was predicted that its ability to attenuate cocaine- and MDMA-induced taste avoidance would parallel the effects of methylone pre-exposure in this design (cocaine > MDMA). In Experiment 1, male Sprague-Dawley rats were exposed to eutylone (20 mg/kg, IP) or equivolume saline every other day for five exposures followed by taste avoidance conditioning with 20 mg/kg cocaine (SC) or 1.8 mg/kg MDMA (SC). Both cocaine and MDMA induced significant taste avoidance that developed over repeated conditioning trials. Cocaine and MDMA-induced avoidance were unaffected by eutylone history. To assess the general ability of eutylone pre-exposure to attenuate taste avoidance conditioning in the pre-exposure design, in Experiment 2, an additional set of male Sprague-Dawley rats was injected with 20 mg/kg eutylone (IP) prior to taste avoidance conditioning with eutylone (20 mg/kg (IP). Under these conditions, eutylone-induced avoidance was attenuated by eutylone pre-exposure. Given that eutylone history attenuated eutylone-induced avoidance argues that the failure to affect cocaine or MDMA was not a function of eutylone in this preparation. The inability of eutylone to attenuate the aversive effects of cocaine and MDMA despite sharing pharmacological activity suggests that eutylone's hybrid pharmacology may create a unique interoceptive effect different than that produced by either drug.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174013"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-04-20DOI: 10.1016/j.pbb.2025.174014
Wenhao Zhang , Zhifu Ai , Genhua Zhu , Ming Yang , Yali Liu , Huanhua Xu , Qin Zheng , Yonggui Song , Dan Su
Currently, Drosophila is widely used to study brain diseases. Unfortunately, Drosophila still lacks a mature and stable model for research on depression. This study addressed this issue by systematically exploring external stress and intrinsic susceptibility factors (Drosophila strains, adult/larval forms) that may influence the establishment and reproducibility of the stress-induced model. On this basis, the parameters are optimized. The results indicate Drosophila strains and forms are critical factors influencing model establishment, while external stress is the primary cause affecting the model's mortality rate. Compared with the other four strains, Canton-S are the most susceptible to chronic unpredictable mild stress (CUMS). Larval forms exhibit lower reactivity to external stress compared to adults. Parameter variations greatly influence model mortality rates from cold/heat/starvation stress. The model methodology validation study conducted subsequently through assessments of face, construct, and predictive validity demonstrates that the model exhibits face (neurobehavioral differences), structural (neurotransmitter changes in the Drosophila brain), and predictive (behavioral changes after fluoxetine treatment) validity. Additionally, spatial behavior experiments in Drosophila provide more realistic activity patterns compared to planar behavior, minimizing potential errors in interpreting lateral movements of the Drosophila, and it is recommended that this metric be included in model evaluation. This study presents a comprehensive set of methods for establishing and evaluating a depression-like behavior model and offers greater convenience for research on the pathogenesis of depression, as well as the screening, efficacy evaluation, and mechanistic studies of antidepressant drugs.
{"title":"Drosophila model of depression-like behavior: systematic investigation of external stress parameters and intrinsic susceptibility","authors":"Wenhao Zhang , Zhifu Ai , Genhua Zhu , Ming Yang , Yali Liu , Huanhua Xu , Qin Zheng , Yonggui Song , Dan Su","doi":"10.1016/j.pbb.2025.174014","DOIUrl":"10.1016/j.pbb.2025.174014","url":null,"abstract":"<div><div>Currently, <em>Drosophila</em> is widely used to study brain diseases. Unfortunately, <em>Drosophila</em> still lacks a mature and stable model for research on depression. This study addressed this issue by systematically exploring external stress and intrinsic susceptibility factors (<em>Drosophila</em> strains, adult/larval forms) that may influence the establishment and reproducibility of the stress-induced model. On this basis, the parameters are optimized. The results indicate <em>Drosophila</em> strains and forms are critical factors influencing model establishment, while external stress is the primary cause affecting the model's mortality rate. Compared with the other four strains, Canton-S are the most susceptible to chronic unpredictable mild stress (CUMS). Larval forms exhibit lower reactivity to external stress compared to adults. Parameter variations greatly influence model mortality rates from cold/heat/starvation stress. The model methodology validation study conducted subsequently through assessments of face, construct, and predictive validity demonstrates that the model exhibits face (neurobehavioral differences), structural (neurotransmitter changes in the <em>Drosophila</em> brain), and predictive (behavioral changes after fluoxetine treatment) validity. Additionally, spatial behavior experiments in <em>Drosophila</em> provide more realistic activity patterns compared to planar behavior, minimizing potential errors in interpreting lateral movements of the <em>Drosophila</em>, and it is recommended that this metric be included in model evaluation. This study presents a comprehensive set of methods for establishing and evaluating a depression-like behavior model and offers greater convenience for research on the pathogenesis of depression, as well as the screening, efficacy evaluation, and mechanistic studies of antidepressant drugs.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"252 ","pages":"Article 174014"},"PeriodicalIF":3.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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