Pub Date : 2025-10-01Epub Date: 2025-08-05DOI: 10.1016/j.pbb.2025.174077
Javad Riyahi , Parvaneh Shamsipour Dehkordi , Behrouz Abdoli , Francesca Gelfo , Laura Petrosini , Abbas Haghparast
Following previous studies on the intergenerational transmission of cognitive abilities, the present research aimed to answer whether parental training on a specific cognitive task may facilitate the learning process of other cognitive tasks in the next generation. Namely, to investigate whether in addition to improving spatial memory acquisition in male offspring, paternal spatial training can also lead to improvements in working memory, short-term memory, and long-term memory, we tested in Morris Water Maze (MWM) or Y-maze and Novel Object Recognition (NOR) tests groups of male offspring of fathers spatially trained (or not spatially trained) in the MWM. Then, we analyzed the immunocontent levels of BDNF, p-ERK1/2, SYT1, and acetylated H3K14 in the hippocampus of the offspring performing MWM, or Y-maze and NOR tests. Paternal MWM training facilitated learning and memory processes of the male offspring in the MWM task, and in parallel, increased hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and also H3K14 acetylation. On the other hand, the paternal MWM training did not affect the processes of working memory, short-term, and long-term memory of the male offspring, and did not change the hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and H3K14 acetylation level after cognitive training. Overall, the present results show that the intergenerational effects of paternal training in cognitive tasks are task-specific, not causing improvements in cognitive tasks other than those in which the fathers had been trained.
{"title":"The task-specific intergenerational transmission of paternal cognitive experiences on male offspring memory","authors":"Javad Riyahi , Parvaneh Shamsipour Dehkordi , Behrouz Abdoli , Francesca Gelfo , Laura Petrosini , Abbas Haghparast","doi":"10.1016/j.pbb.2025.174077","DOIUrl":"10.1016/j.pbb.2025.174077","url":null,"abstract":"<div><div>Following previous studies on the intergenerational transmission of cognitive abilities, the present research aimed to answer whether parental training on a specific cognitive task may facilitate the learning process of other cognitive tasks in the next generation. Namely, to investigate whether in addition to improving spatial memory acquisition in male offspring, paternal spatial training can also lead to improvements in working memory, short-term memory, and long-term memory, we tested in Morris Water Maze (MWM) or Y-maze and Novel Object Recognition (NOR) tests groups of male offspring of fathers spatially trained (or not spatially trained) in the MWM. Then, we analyzed the immunocontent levels of BDNF, p-ERK1/2, SYT1, and acetylated H3K14 in the hippocampus of the offspring performing MWM, or Y-maze and NOR tests. Paternal MWM training facilitated learning and memory processes of the male offspring in the MWM task, and in parallel, increased hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and also H3K14 acetylation. On the other hand, the paternal MWM training did not affect the processes of working memory, short-term, and long-term memory of the male offspring, and did not change the hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and H3K14 acetylation level after cognitive training. Overall, the present results show that the intergenerational effects of paternal training in cognitive tasks are task-specific, not causing improvements in cognitive tasks other than those in which the fathers had been trained.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174077"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789670","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 : 2025-10-01Epub Date: 2025-08-02DOI: 10.1016/j.pbb.2025.174076
Marie Ohno, Haruka Nakamura, Naoto Sakai, Maju Nammoku, Kanzo Suzuki, Eri Segi-Nishida
Calbindin-D28K (Calb1) is a calcium-binding protein that regulates intracellular calcium signaling and neuronal excitability. In the hippocampal dentate gyrus (DG), Calb1 expression increases with granule cell maturation but is downregulated following chronic antidepressant treatment. To elucidate the functional relevance of this antidepressant-associated downregulation, we used an adeno-associated virus-mediated knockdown approach in mice to reduce Calb1 expression in the DG. Calb1 knockdown significantly reduced the expression of FosB, an activity-dependent marker, under basal conditions and impaired neurogenesis by suppressing neural stem/progenitor cell proliferation and delaying neuronal maturation. Behavioral analyses revealed that Calb1 knockdown mice displayed heightened anxiety-associated behavior and reduced social interaction, whereas locomotor activity remained unaffected. These findings suggest that Calb1 expression in the DG supports basal activity-dependent responses, adult neurogenesis and emotional-social behavior. Paradoxically, while chronic antidepressant treatment reduces Calb1 expression, our results indicate that maintaining Calb1 may be essential for sustaining neurogenesis and proper emotional regulation. This discrepancy highlights the complexity of antidepressant mechanisms and suggests that Calb1 is a key regulator for enhancing hippocampal function and behavioral adaptation.
{"title":"Functional role of dentate gyrus calbindin-D28K in supporting neurogenesis and emotional-social behavior relevant to antidepressant action","authors":"Marie Ohno, Haruka Nakamura, Naoto Sakai, Maju Nammoku, Kanzo Suzuki, Eri Segi-Nishida","doi":"10.1016/j.pbb.2025.174076","DOIUrl":"10.1016/j.pbb.2025.174076","url":null,"abstract":"<div><div>Calbindin-D28K (Calb1) is a calcium-binding protein that regulates intracellular calcium signaling and neuronal excitability. In the hippocampal dentate gyrus (DG), Calb1 expression increases with granule cell maturation but is downregulated following chronic antidepressant treatment. To elucidate the functional relevance of this antidepressant-associated downregulation, we used an adeno-associated virus-mediated knockdown approach in mice to reduce Calb1 expression in the DG. Calb1 knockdown significantly reduced the expression of FosB, an activity-dependent marker, under basal conditions and impaired neurogenesis by suppressing neural stem/progenitor cell proliferation and delaying neuronal maturation. Behavioral analyses revealed that Calb1 knockdown mice displayed heightened anxiety-associated behavior and reduced social interaction, whereas locomotor activity remained unaffected. These findings suggest that Calb1 expression in the DG supports basal activity-dependent responses, adult neurogenesis and emotional-social behavior. Paradoxically, while chronic antidepressant treatment reduces Calb1 expression, our results indicate that maintaining Calb1 may be essential for sustaining neurogenesis and proper emotional regulation. This discrepancy highlights the complexity of antidepressant mechanisms and suggests that Calb1 is a key regulator for enhancing hippocampal function and behavioral adaptation.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174076"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758106","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 : 2025-10-01Epub Date: 2025-07-30DOI: 10.1016/j.pbb.2025.174075
Paula Berbegal-Sáez , Ines Gallego-Landin , Javier Macía , Olga Valverde
Synchronisation of internal biological rhythms with external light-dark cycles is crucial for proper function and survival of the organisms, however modern life often imposes irregular light exposure, disrupting these internal clocks. This study investigated the effects of short-term shifted light-dark cycles on mice daily rhythmicity, and whether these alterations trigger molecular and behavioural changes. We evaluated locomotor activity as well as different behavioural domains and gene expression in the hypothalamus and medial prefrontal cortex. Despite non prominent behavioural impairments, such as anxiety or cognitive deficits, we observed a decreased complexity of locomotor activity patterns of the mice subjected to disrupted light-dark cycles. Molecular alterations included dysregulations in oscillations of core clock genes (Cry2, Per2) and region-dependent disruptions in expression of genes involved in neuroplasticity, neurotransmission, motivation, and stress responses, including Th, Drd1, Gria1&2, Oprk1 and Oxtr. Our study reveals that even brief light cycle shifts can disrupt circadian regulation at the molecular level, despite minimal behavioural changes. This molecular-behavioural discrepancy may suggest a complex adaptive response to drastic short-term light perturbations. Understanding the complex interplay between external light cues and internal biological rhythms regulation is crucial for mitigating the negative consequences of irregular light exposure on physiological processes and overall well-being.
{"title":"Irregular light schedules disrupt daily rhythms and dysregulate genes involved in neuroplasticity, motivation, and stress responses","authors":"Paula Berbegal-Sáez , Ines Gallego-Landin , Javier Macía , Olga Valverde","doi":"10.1016/j.pbb.2025.174075","DOIUrl":"10.1016/j.pbb.2025.174075","url":null,"abstract":"<div><div>Synchronisation of internal biological rhythms with external light-dark cycles is crucial for proper function and survival of the organisms, however modern life often imposes irregular light exposure, disrupting these internal clocks. This study investigated the effects of short-term shifted light-dark cycles on mice daily rhythmicity, and whether these alterations trigger molecular and behavioural changes. We evaluated locomotor activity as well as different behavioural domains and gene expression in the hypothalamus and medial prefrontal cortex. Despite non prominent behavioural impairments, such as anxiety or cognitive deficits, we observed a decreased complexity of locomotor activity patterns of the mice subjected to disrupted light-dark cycles. Molecular alterations included dysregulations in oscillations of core clock genes (<em>Cry2</em>, <em>Per2</em>) and region-dependent disruptions in expression of genes involved in neuroplasticity, neurotransmission, motivation, and stress responses, including <em>Th</em>, <em>Drd1</em>, <em>Gria1&2</em>, <em>Oprk1</em> and <em>Oxtr</em>. Our study reveals that even brief light cycle shifts can disrupt circadian regulation at the molecular level, despite minimal behavioural changes. This molecular-behavioural discrepancy may suggest a complex adaptive response to drastic short-term light perturbations. Understanding the complex interplay between external light cues and internal biological rhythms regulation is crucial for mitigating the negative consequences of irregular light exposure on physiological processes and overall well-being.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174075"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749280","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 : 2025-10-01Epub Date: 2025-07-12DOI: 10.1016/j.pbb.2025.174062
Guanyun Bian , Jian Liu , Yanping Hui , Libo Li , Yaxin Yang , Qiaojun Zhang
Non-motor symptoms such as cognitive deficits are often observed in Parkinson's disease, and the effect of L-3,4-dihydroxyphenylalanin (L-DOPA) treatment on working memory in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc) and underlying mechanisms are unclear. In adult male Sprague-Dawley rats, we found that L-DOPA treatment in SNc-lesioned rats reversed working memory impairment, decreased the firing rate of the lateral habenula (LHb) neurons, increased dopamine (DA) levels in the medial prefrontal cortex (mPFC) and hippocampus, and reversed reduced expression of M-channel Kv7.2 subunit in the LHb compared with SNc-lesioned rats treated with normal saline (NS). Intra-LHb injection of M-channel activator retigabine or blocker XE-991 induced enhancement or impairment of working memory in SNc-lesioned rats treated with L-DOPA, along with alterations of DA levels in the mPFC and hippocampus. However, the same doses of the two drugs produced no significant effects on working memory and DA levels in SNc-lesioned rats treated with NS. Further, M-channel activate or blockade decreased or increased the firing rate of LHb neurons, and the duration of M-channel stimulation on the firing rate of the neurons in SNc-lesioned rats treated L-DOPA was longer than those in SNc-lesioned rats treated with NS, which was consistent with up-regulation of Kv7.2 subunit in the LHb. Collectively, these findings suggest that L-DOPA treatment up-regulates the expression of M-channel Kv7.2 subunit in the LHb, and then induces decreased activity of LHb neurons and increased DA levels in the mPFC and hippocampus, which reverse working memory impairment in parkinsonian rats.
{"title":"L-DOPA reverses the impaired working memory via lateral habenula Kv7.2 subunit-containing M-channels in experimental parkinsonism","authors":"Guanyun Bian , Jian Liu , Yanping Hui , Libo Li , Yaxin Yang , Qiaojun Zhang","doi":"10.1016/j.pbb.2025.174062","DOIUrl":"10.1016/j.pbb.2025.174062","url":null,"abstract":"<div><div>Non-motor symptoms such as cognitive deficits are often observed in Parkinson's disease, and the effect of L-3,4-dihydroxyphenylalanin (L-DOPA) treatment on working memory in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra compacta (SNc) and underlying mechanisms are unclear. In adult male Sprague-Dawley rats, we found that L-DOPA treatment in SNc-lesioned rats reversed working memory impairment, decreased the firing rate of the lateral habenula (LHb) neurons, increased dopamine (DA) levels in the medial prefrontal cortex (mPFC) and hippocampus, and reversed reduced expression of M-channel Kv7.2 subunit in the LHb compared with SNc-lesioned rats treated with normal saline (NS). Intra-LHb injection of M-channel activator retigabine or blocker XE-991 induced enhancement or impairment of working memory in SNc-lesioned rats treated with L-DOPA, along with alterations of DA levels in the mPFC and hippocampus. However, the same doses of the two drugs produced no significant effects on working memory and DA levels in SNc-lesioned rats treated with NS. Further, M-channel activate or blockade decreased or increased the firing rate of LHb neurons, and the duration of M-channel stimulation on the firing rate of the neurons in SNc-lesioned rats treated L-DOPA was longer than those in SNc-lesioned rats treated with NS, which was consistent with up-regulation of Kv7.2 subunit in the LHb. Collectively, these findings suggest that L-DOPA treatment up-regulates the expression of M-channel Kv7.2 subunit in the LHb, and then induces decreased activity of LHb neurons and increased DA levels in the mPFC and hippocampus, which reverse working memory impairment in parkinsonian rats.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174062"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144626938","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 : 2025-10-01Epub Date: 2025-07-15DOI: 10.1016/j.pbb.2025.174071
Gauri Vishen Singh , Chetna , Amarjot Kaur Grewal , Ojashvi Sharma , Amit Kumar , Heena Khan , Varinder Singh , Pragati Silakari , Thakur Gurjeet Singh , Tanveer Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua
Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes, via disrupted cellular homeostasis, corticosterone and altered neurotransmitter dynamics. The PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase)-TFEB (Transcription factor EB) pathway integrates stress responses with autophagy and lysosomal biogenesis to maintain cellular resilience, influencing oxidative stress, neuroinflammation and neurodegeneration. Hence, this study was intended to explore the possible involvement of PERK-TFEB pathway in mediating the neuroprotective effects of SB202190 (a PERK activator) in mitigating neurobehavioral changes induced by CUS. For evaluating the impact pharmacological interventions on neurobehavioral alterations, the Swiss albino either sex mice were subjected to different stressors for 8 weeks. The parameters for anxiety-like behaviour, depressive-like behaviour and memory impairment were assessed by elevated plus maze, sucrose preference test, tail suspension test, forced swim test, Morris water maze and passive avoidance task. The levels of corticosterone, dopamine, serotonin, biochemical parameters of oxidative stress, inflammatory mediators, and acetylcholinesterase (AChE) activity along with the histological changes were also examined. Administration of SB202190 (5 and 10 mg/kg) improved anxiety-like behaviour, depression-like behaviour, spatial learning and memory retention, histological changes; restored corticosterone, dopamine levels, AChE activity, oxidative stress and inflammatory markers and serotonin levels in CUS-exposed mice compared to controls. Molecular docking studies were carried out to reveal the binding interaction of SB202190 with TFEB, suggesting that it may modulate TFEB activity. It was also observed that these neuroprotective effects of SB202190 were significantly abolished by pre-treatment with eltrombopag (50 mg/kg, p.o.), a TFEB inhibitor, which signifies the involvement of TFEB signalling in protective mechanism of SB202190 that may have resulted in enhancement of TFEB-mediated autophagy. Therefore, this study highlights the critical role of PERK- TFEB pathway in neuroprotection as well as highlights mechanism and therapeutic potential of SB202190 in alleviating neurobehavioral changes and memory dysfunction associated with chronic unpredictable stress.
{"title":"PERK activation mediates neuroprotection against chronic unpredictable stress-induced neurobehavioral changes via the TFEB pathway","authors":"Gauri Vishen Singh , Chetna , Amarjot Kaur Grewal , Ojashvi Sharma , Amit Kumar , Heena Khan , Varinder Singh , Pragati Silakari , Thakur Gurjeet Singh , Tanveer Singh , Sheikh F. Ahmad , Haneen A. Al-Mazroua","doi":"10.1016/j.pbb.2025.174071","DOIUrl":"10.1016/j.pbb.2025.174071","url":null,"abstract":"<div><div>Chronic unpredictable stress (CUS) is a significant contributor to neurobehavioral changes, <em>via</em> disrupted cellular homeostasis, corticosterone and altered neurotransmitter dynamics. The PERK (Protein Kinase RNA-like Endoplasmic Reticulum Kinase)-TFEB (Transcription factor EB) pathway integrates stress responses with autophagy and lysosomal biogenesis to maintain cellular resilience, influencing oxidative stress, neuroinflammation and neurodegeneration. Hence, this study was intended to explore the possible involvement of PERK-TFEB pathway in mediating the neuroprotective effects of SB202190 (a PERK activator) in mitigating neurobehavioral changes induced by CUS. For evaluating the impact pharmacological interventions on neurobehavioral alterations, the Swiss albino either sex mice were subjected to different stressors for 8 weeks. The parameters for anxiety-like behaviour, depressive-like behaviour and memory impairment were assessed by elevated plus maze, sucrose preference test, tail suspension test, forced swim test, Morris water maze and passive avoidance task. The levels of corticosterone, dopamine, serotonin, biochemical parameters of oxidative stress, inflammatory mediators, and acetylcholinesterase (AChE) activity along with the histological changes were also examined. Administration of SB202190 (5 and 10 mg/kg) improved anxiety-like behaviour, depression-like behaviour, spatial learning and memory retention, histological changes; restored corticosterone, dopamine levels, AChE activity, oxidative stress and inflammatory markers and serotonin levels in CUS-exposed mice compared to controls. Molecular docking studies were carried out to reveal the binding interaction of SB202190 with TFEB, suggesting that it may modulate TFEB activity. It was also observed that these neuroprotective effects of SB202190 were significantly abolished by pre-treatment with eltrombopag (50 mg/kg, p.o.), a TFEB inhibitor, which signifies the involvement of TFEB signalling in protective mechanism of SB202190 that may have resulted in enhancement of TFEB-mediated autophagy. Therefore, this study highlights the critical role of PERK- TFEB pathway in neuroprotection as well as highlights mechanism and therapeutic potential of SB202190 in alleviating neurobehavioral changes and memory dysfunction associated with chronic unpredictable stress.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174071"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659809","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 : 2025-10-01Epub Date: 2025-07-10DOI: 10.1016/j.pbb.2025.174061
Belle Buzzi , Burhan Buttar , Yasmine Groener , M. Imad Damaj
Commencement of smoking at an early age increases the number of cigarettes smoked per day and decreases the likelihood of successful cessation later in life. To date, little is known about the effects that adolescent nicotine exposure has on aspects of nicotine dependence in adulthood. In this study, we examined the effects of adolescent nicotine exposure on nicotine reward and withdrawal in adulthood. Adolescent mice [postnatal day (PND) 28–34] were exposed to nicotine short-term (0.5 mg/kg, subcutaneous (s.c.) twice a day for one day) or repeatedly (0.1 and 0.5 mg/kg, s.c. twice daily for seven days). In adulthood (PND 70) these mice were implanted with osmotic nicotine minipumps for 14 days and 24 h later spontaneous nicotine withdrawal affective (anxiety-like behavior and hyperalgesia) and physical (somatic signs) signs were assessed. Short-term pre-exposure to nicotine during adolescence did not produce alterations in affective or physical nicotine withdrawal signs in adulthood. However, repeated nicotine exposure during adolescence partially reduced nicotine withdrawal signs in adulthood but increases nicotine reward in the conditioned place preference (CPP) test. Interestingly, adult mice exposed to chronic nicotine (0.5 mg/kg,s.c. twice daily for seven days) did not affect nicotine withdrawal signs and reward later in adulthood. This mouse study highlights nicotine exposure during the unique period of adolescence as an important factor for nicotine dependence later in life.
{"title":"Adolescent nicotine exposure affects later-life nicotine reward and withdrawal in mice","authors":"Belle Buzzi , Burhan Buttar , Yasmine Groener , M. Imad Damaj","doi":"10.1016/j.pbb.2025.174061","DOIUrl":"10.1016/j.pbb.2025.174061","url":null,"abstract":"<div><div>Commencement of smoking at an early age increases the number of cigarettes smoked per day and decreases the likelihood of successful cessation later in life. To date, little is known about the effects that adolescent nicotine exposure has on aspects of nicotine dependence in adulthood. In this study, we examined the effects of adolescent nicotine exposure on nicotine reward and withdrawal in adulthood. Adolescent mice [postnatal day (PND) 28–34] were exposed to nicotine short-term (0.5 mg/kg, subcutaneous (s.c.) twice a day for one day) or repeatedly (0.1 and 0.5 mg/kg, s.c. twice daily for seven days). In adulthood (PND 70) these mice were implanted with osmotic nicotine minipumps for 14 days and 24 h later spontaneous nicotine withdrawal affective (anxiety-like behavior and hyperalgesia) and physical (somatic signs) signs were assessed. Short-term pre-exposure to nicotine during adolescence did not produce alterations in affective or physical nicotine withdrawal signs in adulthood. However, repeated nicotine exposure during adolescence partially reduced nicotine withdrawal signs in adulthood but increases nicotine reward in the conditioned place preference (CPP) test. Interestingly, adult mice exposed to chronic nicotine (0.5 mg/kg,s.c. twice daily for seven days) did not affect nicotine withdrawal signs and reward later in adulthood. This mouse study highlights nicotine exposure during the unique period of adolescence as an important factor for nicotine dependence later in life.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174061"},"PeriodicalIF":3.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144595928","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 : 2025-10-01Epub Date: 2025-08-05DOI: 10.1016/j.pbb.2025.174078
Gang Zhao , Xian Tian , Kangwei Peng , Lin Guo , Yuhuang Chen , Yonggang Cao , Hongmei Wu , Min Zhang
Objective
We investigated the role of sphingosine-1-phosphate receptor 1 (S1PR1) in blood-brain barrier (BBB) function and associated behavioral abnormalities using the BTBR T + tf/J (BTBR) mouse model of autism.
Methods
Male C57BL/6 J (C57) and BTBR mice (4-week-old, n = 16/group) were assigned to three groups: C57 + Veh, BTBR+Veh, and BTBR+W146. The BTBR+W146 group received daily intraperitoneal injections of W146 (1 mg/kg) for 21 days, while control groups received equivalent volumes of vehicle (DMSO+0.9 % saline). Learning and memory were assessed using the Morris water maze. S1PR1 expression was determined via RT-PCR and Western blot analysis. Hippocampal neuronal morphology was examined by Nissl staining, while microvascular endothelial markers (CD31) and apoptotic pathway proteins (p-ERK, Caspase-3) were assessed by immunohistochemistry and Western blot.
Results
BTBR mice showed significantly higher hippocampal S1P and S1PR1 than C57 controls (P < 0.01). W146 treatment reduced escape latency and increased platform crossings in the Morris water maze (P < 0.05). Treatment with W146 also increased phospho-Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), and phospho-cAMP-response element binding protein (p-CREB) expression in the hippocampus. Histologically, W146 restored neuronal density in the hippocampal CA1 region and preserved microvascular integrity, as shown by increased CD31 expression (P < 0.05). The observed neuroprotective effect was linked to significant decreases in the expression of phosphorylated ERK (P < 0.05) and Caspase-3 (P < 0.05).
Conclusion
Elevated S1P/S1PR1 signaling in BTBR mice is associated with hippocampal neurovascular dysfunction. Treatment with the S1PR1 antagonist W146 improves learning and memory deficits, coinciding with reduced ERK/Caspase-3-mediated apoptotic signaling and preserved CA1 neuronal integrity. These findings highlight S1PR1 as a potential therapeutic target for autism-related cognitive impairments.
{"title":"Targeting S1PR1 with W146 Ameliorates autism-associated cognitive deficits by restoring neurovascular integrity via ERK/Caspase-3 pathway modulation","authors":"Gang Zhao , Xian Tian , Kangwei Peng , Lin Guo , Yuhuang Chen , Yonggang Cao , Hongmei Wu , Min Zhang","doi":"10.1016/j.pbb.2025.174078","DOIUrl":"10.1016/j.pbb.2025.174078","url":null,"abstract":"<div><h3>Objective</h3><div>We investigated the role of sphingosine-1-phosphate receptor 1 (S1PR1) in blood-brain barrier (BBB) function and associated behavioral abnormalities using the BTBR T + tf/J (BTBR) mouse model of autism.</div></div><div><h3>Methods</h3><div>Male C57BL/6 J (C57) and BTBR mice (4-week-old, <em>n</em> = 16/group) were assigned to three groups: C57 + Veh, BTBR+Veh, and BTBR+W146. The BTBR+W146 group received daily intraperitoneal injections of W146 (1 mg/kg) for 21 days, while control groups received equivalent volumes of vehicle (DMSO+0.9 % saline). Learning and memory were assessed using the Morris water maze. S1PR1 expression was determined via RT-PCR and Western blot analysis. Hippocampal neuronal morphology was examined by Nissl staining, while microvascular endothelial markers (CD31) and apoptotic pathway proteins (p-ERK, Caspase-3) were assessed by immunohistochemistry and Western blot.</div></div><div><h3>Results</h3><div>BTBR mice showed significantly higher hippocampal S1P and S1PR1 than C57 controls (<em>P</em> < 0.01). W146 treatment reduced escape latency and increased platform crossings in the Morris water maze (<em>P</em> < 0.05). Treatment with W146 also increased phospho-Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (p-CaMKII), and phospho-cAMP-response element binding protein (p-CREB) expression in the hippocampus. Histologically, W146 restored neuronal density in the hippocampal CA1 region and preserved microvascular integrity, as shown by increased CD31 expression (<em>P</em> < 0.05). The observed neuroprotective effect was linked to significant decreases in the expression of phosphorylated ERK (<em>P</em> < 0.05) and Caspase-3 (<em>P</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>Elevated S1P/S1PR1 signaling in BTBR mice is associated with hippocampal neurovascular dysfunction. Treatment with the S1PR1 antagonist W146 improves learning and memory deficits, coinciding with reduced ERK/Caspase-3-mediated apoptotic signaling and preserved CA1 neuronal integrity. These findings highlight S1PR1 as a potential therapeutic target for autism-related cognitive impairments.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174078"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780616","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 : 2025-10-01Epub Date: 2025-07-24DOI: 10.1016/j.pbb.2025.174072
Madeline K. Elsey , Nina M. Beltran , Katherine M. Serafine
High fat diets are linked to several negative health consequences in humans including disrupted insulin signaling, and research with rodents has demonstrated that these diets can also increase individual sensitivity to drugs that act on dopamine systems. Since ketogenic diets have different effects on weight and insulin signaling than traditional high fat diets, it was hypothesized that a ketogenic diet (high in fat but very low in carbohydrates) might not increase sensitivity of rats to dopaminergic drugs. To test this hypothesis rats eating standard chow (17 % kcal from fat), high fat chow (60 % kcal from fat), or ketogenic chow (90.5 % kal from fat) were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or methamphetamine (0.1–3.2 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and methamphetamine. While eating a ketogenic chow did not impact sensitivity to quinpirole, rats eating ketogenic chow were more sensitive than rats eating standard chow to methamphetamine-induced locomotion, but only at the largest cumulative dose tested. These results suggest that traditional high fat diets and ketogenic diets might produce similar, but non-identical effects on sensitivity to the behavioral effects of dopaminergic drugs.
{"title":"Eating a ketogenic diet enhances sensitivity of rats to the effects of methamphetamine, but not dopamine D2/D3 receptor agonist quinpirole","authors":"Madeline K. Elsey , Nina M. Beltran , Katherine M. Serafine","doi":"10.1016/j.pbb.2025.174072","DOIUrl":"10.1016/j.pbb.2025.174072","url":null,"abstract":"<div><div>High fat diets are linked to several negative health consequences in humans including disrupted insulin signaling, and research with rodents has demonstrated that these diets can also increase individual sensitivity to drugs that act on dopamine systems. Since ketogenic diets have different effects on weight and insulin signaling than traditional high fat diets, it was hypothesized that a ketogenic diet (high in fat but very low in carbohydrates) might not increase sensitivity of rats to dopaminergic drugs. To test this hypothesis rats eating standard chow (17 % kcal from fat), high fat chow (60 % kcal from fat), or ketogenic chow (90.5 % kal from fat) were tested once weekly with quinpirole [0.0032–0.32 mg/kg, intraperitoneally (i.p.)] or methamphetamine (0.1–3.2 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and methamphetamine. While eating a ketogenic chow did not impact sensitivity to quinpirole, rats eating ketogenic chow were more sensitive than rats eating standard chow to methamphetamine-induced locomotion, but only at the largest cumulative dose tested. These results suggest that traditional high fat diets and ketogenic diets might produce similar, but non-identical effects on sensitivity to the behavioral effects of dopaminergic drugs.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174072"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718303","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 : 2025-10-01Epub Date: 2025-07-04DOI: 10.1016/j.pbb.2025.174060
Rafaela Mostallino , Francesca Caria , Aurora Musa , Gessica Piras , Anastasija Ture , Maksims Vanejevs , Antonio Laus , Graziella Tocco , Gaetano Di Chiara , M. Paola Castelli , Maria Antonietta De Luca
The development of new μ-opioid receptor (MOR) antagonists has been stimulated by the opioid overdose crisis. Our earlier in silico investigations on ligand-MOR receptor interactions indicated that the ligand cis-equatorial conformation of the amine and phenol is the most likely orientation observed within the MOR receptor. Here, we synthesized and characterized AT-99 [3-(1,3-dimethyl-cis-5-(methyl(phenethyl)amino)cyclohexyl)phenol] as a new in vivo and in vitro MOR antagonist. AT-99 effectively blocked MOR-mediated G protein activation by the agonists fentanyl and DAMGO, similarly to the reference compound, the opioid antagonist naloxone (NAL). Moreover, AT-99 behaves as a neutral MOR antagonist since it failed to stimulate [35S]GTPγS binding, but it dose-dependently inhibited DAMGO-induced [35S]GTPγS binding. While 0.1 μM NAL significantly reduced DAMGO potency, AT-99 produced a comparable effect only at the highest concentration tested. Furthermore, in radioligand competition binding assays, AT-99 fully displaced specific [3H]DAMGO binding in a concentration-dependent manner, although with lower affinity than NAL. In vivo, AT-99 (1 or 3 mg/kg i.v.) dose-dependently reduced the increase of dialysate dopamine (DA) in the nucleus accumbens (NAc) shell induced by morphine (1 mg/kg i.v.). Notably, AT-99 at the highest dose tested counteracted the reduction of behavioral rating scale (BRS) induced by morphine. Altogether, these data indicate that, although AT-99 interacts with the MOR relatively weakly, it displays interesting MOR antagonist properties, and as such it might serve as a scaffold to develop more potent MOR antagonists.
{"title":"The novel synthesized naltrexone-related MOR antagonist AT-99 counteracts dopamine releasing and behavioral depressant morphine-induced effects","authors":"Rafaela Mostallino , Francesca Caria , Aurora Musa , Gessica Piras , Anastasija Ture , Maksims Vanejevs , Antonio Laus , Graziella Tocco , Gaetano Di Chiara , M. Paola Castelli , Maria Antonietta De Luca","doi":"10.1016/j.pbb.2025.174060","DOIUrl":"10.1016/j.pbb.2025.174060","url":null,"abstract":"<div><div>The development of new μ-opioid receptor (MOR) antagonists has been stimulated by the opioid overdose crisis. Our earlier <em>in silico</em> investigations on ligand-MOR receptor interactions indicated that the ligand cis-equatorial conformation of the amine and phenol is the most likely orientation observed within the MOR receptor. Here, we synthesized and characterized AT-99 [3-(1,3-dimethyl-<em>cis</em>-5-(methyl(phenethyl)amino)cyclohexyl)phenol] as a new <em>in vivo</em> and <em>in vitro</em> MOR antagonist. AT-99 effectively blocked MOR-mediated G protein activation by the agonists fentanyl and DAMGO, similarly to the reference compound, the opioid antagonist naloxone (NAL). Moreover, AT-99 behaves as a neutral MOR antagonist since it failed to stimulate [<sup>35</sup>S]GTPγS binding, but it dose-dependently inhibited DAMGO-induced [<sup>35</sup>S]GTPγS binding. While 0.1 μM NAL significantly reduced DAMGO potency, AT-99 produced a comparable effect only at the highest concentration tested. Furthermore, in radioligand competition binding assays, AT-99 fully displaced specific [<sup>3</sup>H]DAMGO binding in a concentration-dependent manner, although with lower affinity than NAL. <em>In vivo</em>, AT-99 (1 or 3 mg/kg i.v.) dose-dependently reduced the increase of dialysate dopamine (DA) in the nucleus accumbens (NAc) shell induced by morphine (1 mg/kg i.v.). Notably, AT-99 at the highest dose tested counteracted the reduction of behavioral rating scale (BRS) induced by morphine. Altogether, these data indicate that, although AT-99 interacts with the MOR relatively weakly, it displays interesting MOR antagonist properties, and as such it might serve as a scaffold to develop more potent MOR antagonists.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174060"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576019","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 : 2025-09-01Epub Date: 2025-07-02DOI: 10.1016/j.pbb.2025.174057
Shuang Wang , Yuning Wang , Li Meng , Haishui Shi , Xueyong Yin , Hao Feng , Xincheng Li , Xiaoyu Liu , Yun Shi , Yuan Gao
Chronic stress has been widely reported to be related to alterations in emotional behaviors of individuals, yet the potential effects of post-weaning stress (PWS) and the associated mechanisms are still poorly understood. Mitochondria-associated endoplasmic reticulum membranes (MAM) play crucial roles in cellular energy metabolism, calcium homeostasis, lipid synthesis, and have been highlighted in recent studies for their importance in the nervous system. This study aims to explore how PWS affects behaviors, especially aggressive behavior and social hierarchy, and whether MAM plays a role in this process in ICR mice.
Various behavioral assessments were employed to measure different behaviors: the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the resident-intruder test (RIT) and defensive aggression test (DAT) for aggressive behavior, and the social dominance test (SDT) to evaluate social hierarchy. Transmission electron microscopy and Immunofluorescence staining were used to analyze the MAM structure in the neurons of hypothalamus, a crucial brain region that regulates the various behaviors described above. The findings indicated that PWS reduced weight gain and elevated social hierarchy in male mice. Behavioral effects were assay-specific: aggression decreased in the RIT (attack frequency/time) but not the DAT, while anxiety-like behaviors showed mixed results (increased open-arm exploration in EPM but no OFT changes). Females exhibited reduced locomotion without aggression or anxiety alterations. Notably, a decrease in mitochondrial-endoplasmic reticulum contact was observed, accompanied by decreased voltage-dependent anion channel 1 (VDAC1) in males and increased inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in females. These alterations may influence energy metabolism and stress responses, potentially contributing to the observed behavioral changes. These findings emphasize the importance of understanding the neurobiological underpinnings of aggression and stress response, particularly in relation to stress experienced during early life.
{"title":"Post-weaning unpredictable mild stress affects social behaviors and mitochondria-associated endoplasmic reticulum membranes in adult mice","authors":"Shuang Wang , Yuning Wang , Li Meng , Haishui Shi , Xueyong Yin , Hao Feng , Xincheng Li , Xiaoyu Liu , Yun Shi , Yuan Gao","doi":"10.1016/j.pbb.2025.174057","DOIUrl":"10.1016/j.pbb.2025.174057","url":null,"abstract":"<div><div>Chronic stress has been widely reported to be related to alterations in emotional behaviors of individuals, yet the potential effects of post-weaning stress (PWS) and the associated mechanisms are still poorly understood. Mitochondria-associated endoplasmic reticulum membranes (MAM) play crucial roles in cellular energy metabolism, calcium homeostasis, lipid synthesis, and have been highlighted in recent studies for their importance in the nervous system. This study aims to explore how PWS affects behaviors, especially aggressive behavior and social hierarchy, and whether MAM plays a role in this process in ICR mice.</div><div>Various behavioral assessments were employed to measure different behaviors: the open field test (OFT) and elevated plus maze (EPM) for anxiety-like behavior, the resident-intruder test (RIT) and defensive aggression test (DAT) for aggressive behavior, and the social dominance test (SDT) to evaluate social hierarchy. Transmission electron microscopy and Immunofluorescence staining were used to analyze the MAM structure in the neurons of hypothalamus, a crucial brain region that regulates the various behaviors described above. The findings indicated that PWS reduced weight gain and elevated social hierarchy in male mice. Behavioral effects were assay-specific: aggression decreased in the RIT (attack frequency/time) but not the DAT, while anxiety-like behaviors showed mixed results (increased open-arm exploration in EPM but no OFT changes). Females exhibited reduced locomotion without aggression or anxiety alterations. Notably, a decrease in mitochondrial-endoplasmic reticulum contact was observed, accompanied by decreased voltage-dependent anion channel 1 (VDAC1) in males and increased inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in females. These alterations may influence energy metabolism and stress responses, potentially contributing to the observed behavioral changes. These findings emphasize the importance of understanding the neurobiological underpinnings of aggression and stress response, particularly in relation to stress experienced during early life.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174057"},"PeriodicalIF":3.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565086","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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