Pub 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":"2025-08-02","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 : 2025-07-30DOI: 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":"2025-07-30","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 : 2025-07-29DOI: 10.1016/j.pbb.2025.174074
Ran An , Baoyao Gao , Lei Xiao , Zhenhua Wang , Zijun Liu , Xingyao Chen , Hongyan Qian , Yonghong Liu , Yunlong Sun , Tao Li , Jianbo Zhang , Xinshe Liu
Carfentanil is a widely used opioid new psychoactive substance (NPS) that possesses a high risk of addiction. However, the positive and negative reinforcement, as well as the psychostimulant effects of carfentanil remain unclear. In the present study, we compared the rewarding (positive reinforcement) and psychostimulant effects between carfentanil and morphine, using the conditioned place preference (CPP, including acquisition, extinction, and reinstatement) and behavioral sensitization paradigms. The withdrawal syndrome and anxiety- and depressive-like behaviors were detected to reveal the drug withdrawal-induced somatic and psychiatric symptoms (associated with negative reinforcement). Our results demonstrated that a low dose (0.5 μg/kg) of carfentanil could induce comparable CPP acquisition to 10 mg/kg morphine. Carfentanil, but not morphine, successfully induced behavioral sensitization. Both carfentanil and morphine withdrawal led to somatic and psychiatric (anxiety- and depressive- like behaviors) symptoms. Notably, carfentanil-exposed mice demonstrated more severe somatic withdrawal symptoms compared to morphine-exposed mice after naloxone-precipitation. In the drug-induced acquisition of CPP, carfentanil-exposed mice, but not morphine-exposed mice, showed an increase of c-Fos expression in the shell of nucleus accumbens (NAcSh) and caudate putamen (CPu). In the naloxone-precipitated drug withdrawal, carfentanil-exposed mice exhibited a higher level of c-Fos expression than morphine-exposed mice in the CPu. Carfentanil, but not morphine, activated the prefrontal cortex (PFC), NAcSh, and dorsal hippocampus (dHPC). Collectively, we found more potent reinforcing and psychostimulant effects of carfentanil compared to morphine. Our findings extend the knowledge and lay the foundation for the mechanistic studies of the reinforcing and psychostimulant effects of NPSs.
{"title":"Reinforcing and psychostimulant effects of carfentanil and morphine in mice","authors":"Ran An , Baoyao Gao , Lei Xiao , Zhenhua Wang , Zijun Liu , Xingyao Chen , Hongyan Qian , Yonghong Liu , Yunlong Sun , Tao Li , Jianbo Zhang , Xinshe Liu","doi":"10.1016/j.pbb.2025.174074","DOIUrl":"10.1016/j.pbb.2025.174074","url":null,"abstract":"<div><div>Carfentanil is a widely used opioid new psychoactive substance (NPS) that possesses a high risk of addiction. However, the positive and negative reinforcement, as well as the psychostimulant effects of carfentanil remain unclear. In the present study, we compared the rewarding (positive reinforcement) and psychostimulant effects between carfentanil and morphine, using the conditioned place preference (CPP, including acquisition, extinction, and reinstatement) and behavioral sensitization paradigms. The withdrawal syndrome and anxiety- and depressive-like behaviors were detected to reveal the drug withdrawal-induced somatic and psychiatric symptoms (associated with negative reinforcement). Our results demonstrated that a low dose (0.5 μg/kg) of carfentanil could induce comparable CPP acquisition to 10 mg/kg morphine. Carfentanil, but not morphine, successfully induced behavioral sensitization. Both carfentanil and morphine withdrawal led to somatic and psychiatric (anxiety- and depressive- like behaviors) symptoms. Notably, carfentanil-exposed mice demonstrated more severe somatic withdrawal symptoms compared to morphine-exposed mice after naloxone-precipitation. In the drug-induced acquisition of CPP, carfentanil-exposed mice, but not morphine-exposed mice, showed an increase of c-Fos expression in the shell of nucleus accumbens (NAcSh) and caudate putamen (CPu). In the naloxone-precipitated drug withdrawal, carfentanil-exposed mice exhibited a higher level of c-Fos expression than morphine-exposed mice in the CPu. Carfentanil, but not morphine, activated the prefrontal cortex (PFC), NAcSh, and dorsal hippocampus (dHPC). Collectively, we found more potent reinforcing and psychostimulant effects of carfentanil compared to morphine. Our findings extend the knowledge and lay the foundation for the mechanistic studies of the reinforcing and psychostimulant effects of NPSs.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174074"},"PeriodicalIF":2.5,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144739209","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 : 2025-07-25DOI: 10.1016/j.pbb.2025.174073
Megan Stout, Ella Andonov, Amir H. Rezvani, Edward D. Levin
Nicotine has been found by a variety of studies to improve cognitive function, including attention in both humans and experimental animals. However, it is not known which nicotinic acetylcholine receptor (nAChR) stimulating vs. desensitizing effects of nicotine are responsible for the cognitive improvement. Young adult female Sprague-Dawley rats were trained on an operant visual signal detection task to assess sustained attention. Then, they were administered nicotine subcutaneously (sc) in low doses of 0, 0.01, 0.02 or 0.04 mg/kg (N = 10–11/group), 20 min before the test sessions. In the next phase, nicotine or vehicle saline was given alone or in combination with doses of 4 and 8 mg/kg (sc) of dihydro-β-erythroidine (DHβE), an α4β2 nicotinic receptor antagonist or methyllycaconitine (MLA), an α7 nicotinic receptor antagonist, to determine whether any effects caused by nicotine would be blocked by co-administration of these nAChR antagonists. Our results show that both 0.01 mg/kg and 0.04 mg/kg nicotine doses caused modest, but significant improvement in percent correct on the attentional test relative to control rats, while the 0.02 mg/kg nicotine dose had a marginal (p < 0.10) improvement that did not reach statistical significance. The significant improvement in percent correct performance on the attention test continued to be evident during the second phase of the study in which nAChR antagonists were co-administered. The rats given 0.01 mg/kg of nicotine continued to show a significant improvement in percent correct relative to the saline vehicle even in the face of the higher dose of each nicotinic antagonist. Our results show that low dose nicotine-induced attentional performance was not reversed by specific nAChR antagonists such as DHβE and MLA. This is consistent with the hypothesis that the nAChR desensitizing effect of nicotine, with low dose of nicotine, rather than the receptor stimulatory effect of nicotine underlies its action of improving attentional performance.
{"title":"Low dose nicotine administration improves attentional performance in rats but is not blocked by nicotinic antagonists","authors":"Megan Stout, Ella Andonov, Amir H. Rezvani, Edward D. Levin","doi":"10.1016/j.pbb.2025.174073","DOIUrl":"10.1016/j.pbb.2025.174073","url":null,"abstract":"<div><div>Nicotine has been found by a variety of studies to improve cognitive function, including attention in both humans and experimental animals. However, it is not known which nicotinic acetylcholine receptor (nAChR) stimulating vs. desensitizing effects of nicotine are responsible for the cognitive improvement. Young adult female Sprague-Dawley rats were trained on an operant visual signal detection task to assess sustained attention. Then, they were administered nicotine subcutaneously (sc) in low doses of 0, 0.01, 0.02 or 0.04 mg/kg (<em>N</em> = 10–11/group), 20 min before the test sessions. In the next phase, nicotine or vehicle saline was given alone or in combination with doses of 4 and 8 mg/kg (sc) of dihydro-β-erythroidine (DHβE), an α4β2 nicotinic receptor antagonist or methyllycaconitine (MLA), an α7 nicotinic receptor antagonist, to determine whether any effects caused by nicotine would be blocked by co-administration of these nAChR antagonists. Our results show that both 0.01 mg/kg and 0.04 mg/kg nicotine doses caused modest, but significant improvement in percent correct on the attentional test relative to control rats, while the 0.02 mg/kg nicotine dose had a marginal (<em>p</em> < 0.10) improvement that did not reach statistical significance. The significant improvement in percent correct performance on the attention test continued to be evident during the second phase of the study in which nAChR antagonists were co-administered. The rats given 0.01 mg/kg of nicotine continued to show a significant improvement in percent correct relative to the saline vehicle even in the face of the higher dose of each nicotinic antagonist. Our results show that low dose nicotine-induced attentional performance was not reversed by specific nAChR antagonists such as DHβE and MLA. This is consistent with the hypothesis that the nAChR desensitizing effect of nicotine, with low dose of nicotine, rather than the receptor stimulatory effect of nicotine underlies its action of improving attentional performance.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174073"},"PeriodicalIF":2.5,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732663","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 : 2025-07-24DOI: 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":"2025-07-24","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 : 2025-07-15DOI: 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":"2025-07-15","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 : 2025-07-12DOI: 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":"2025-07-12","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 : 2025-07-10DOI: 10.1016/j.pbb.2025.174063
Shannon M. Lopez , Magdalena R. Gonzales , Bryan D. Alvarez , Leslie R. Amodeo , Dionisio A. Amodeo
The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.
{"title":"Repeated 5-HT6 receptor activation facilitates flexible behavior in C57BL/6J mice","authors":"Shannon M. Lopez , Magdalena R. Gonzales , Bryan D. Alvarez , Leslie R. Amodeo , Dionisio A. Amodeo","doi":"10.1016/j.pbb.2025.174063","DOIUrl":"10.1016/j.pbb.2025.174063","url":null,"abstract":"<div><div>The serotonin (5-HT) 6 receptor has recently emerged as a novel target for the treatment of cognitive deficits seen in known neuropsychiatric disorders. While much of the research has concentrated on understanding the therapeutic effects of 5-HT6 receptor antagonists, much less is known regarding the behavioral impact of 5-HT6 agonist treatment. The current study examined the impact of 5-HT6 receptor partial agonist EMD 386088 on behavioral flexibility in an operant probabilistic reversal learning paradigm. Female and male C57BL/6J mice were trained on an 80 %/20 % probabilistic discrimination task until the learning criterion was reached. As predicted, mice did not differ in trials or days to reach criterion during this initial acquisition phase. Once the learning criterion was met, the probabilistic 80 %/20 % contingencies were reversed. Mice received EMD 386088 (1 or 5 mg/kg) or vehicle control administration before each reversal learning session. Mice treated with 1 mg/kg EMD 386088 took significantly fewer trials to reach reversal learning criterion compared to controls. Conversely, the 5 mg/kg dosage did not affect trials or days to reach reversal criterion. While EMD 386088 treated female mice tended to display enhanced reversal learning, there were no significant sex differences. Enhanced reversal learning in the 1 mg/kg group coincided with an increase in the probability of win-stay behavior compared to controls. Thus, the 1.0 mg/kg dose of EMD 386088 may lead to an increase the animals' sensitivity to the reinforced trials during learning. These findings highlight the benefits of repeated 5-HT6 receptor activation on facilitating behavioral flexibility.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174063"},"PeriodicalIF":3.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619713","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 : 2025-07-10DOI: 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":"2025-07-10","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 : 2025-07-04DOI: 10.1016/j.pbb.2025.174059
Daniel Bussinger de Souza Penna , Samara Gumiéro Costa , Marina Pollis Davis , Karin da Costa Calaza , Alexandre dos Santos Rodrigues , Pablo Pandolfo
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by impairments in executive functions, including behavioral inhibition and working memory. The most widely accepted neurobiological explanation for ADHD is related to dopaminergic hypofunction. The dopaminergic system is modulated by endocannabinoid ligands, primarily through the action of cannabinoid receptors type 1 and 2 (CB1R and CB2R) within frontostriatal circuits. Spontaneously hypertensive rats (SHR) are a widely used animal model for studying the neurobiology of ADHD. Our recent study demonstrated that acute treatment with synthetic CB1R and CB2R ligands increased hyperactivity and risk-taking behavior in SHR. We now investigate how chronic modulation of these receptors affects hyperactivity, risk-taking behavior, and working memory assessment in SHR. As expected, the SHR exhibited hyperactivity, difficulties in risk assessment, impaired working memory, and increased risk-taking behavior. Notably, females SHR displayed higher levels of locomotion and risk-taking behavior than their male counterparts, regardless of treatment. Chronic modulation of CB1R and CB2R did not lead to significant changes in any of the evaluated behavioral parameters. Further research is needed to understand both the acute and chronic effects of manipulating cannabinoid receptors and endocannabinoids in the context of ADHD.
{"title":"Chronic modulation of endocannabinoid receptors does not impact hyperactivity, risk behavior, and working memory in an animal model of attention-deficit/hyperactivity disorder","authors":"Daniel Bussinger de Souza Penna , Samara Gumiéro Costa , Marina Pollis Davis , Karin da Costa Calaza , Alexandre dos Santos Rodrigues , Pablo Pandolfo","doi":"10.1016/j.pbb.2025.174059","DOIUrl":"10.1016/j.pbb.2025.174059","url":null,"abstract":"<div><div>Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by impairments in executive functions, including behavioral inhibition and working memory. The most widely accepted neurobiological explanation for ADHD is related to dopaminergic hypofunction. The dopaminergic system is modulated by endocannabinoid ligands, primarily through the action of cannabinoid receptors type 1 and 2 (CB1R and CB2R) within frontostriatal circuits. Spontaneously hypertensive rats (SHR) are a widely used animal model for studying the neurobiology of ADHD. Our recent study demonstrated that acute treatment with synthetic CB1R and CB2R ligands increased hyperactivity and risk-taking behavior in SHR. We now investigate how chronic modulation of these receptors affects hyperactivity, risk-taking behavior, and working memory assessment in SHR. As expected, the SHR exhibited hyperactivity, difficulties in risk assessment, impaired working memory, and increased risk-taking behavior. Notably, females SHR displayed higher levels of locomotion and risk-taking behavior than their male counterparts, regardless of treatment. Chronic modulation of CB1R and CB2R did not lead to significant changes in any of the evaluated behavioral parameters. Further research is needed to understand both the acute and chronic effects of manipulating cannabinoid receptors and endocannabinoids in the context of ADHD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"254 ","pages":"Article 174059"},"PeriodicalIF":3.3,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563821","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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