Pharmacology Biochemistry and Behavior最新文献

{"title":"Post-conditioning catecholaminergic antagonism fails to alter methamphetamine sensitization in mice","authors":"A.S. Rauhut ,&nbsp;K. Mehta ,&nbsp;N. Fedorczak ,&nbsp;J. Henderson ,&nbsp;H. Holdaway ,&nbsp;G.B. Rauhut","doi":"10.1016/j.pbb.2025.174129","DOIUrl":"10.1016/j.pbb.2025.174129","url":null,"abstract":"<div><div>Single injection sensitization studies model the early transition to compulsive drug-seeking behavior, independent of other biological processes (e.g., drug tolerance). This paper examined a) the temporal persistence of (Experiment 1), and b) the role of catecholaminergic-mediated post-conditioning memory processes (Experiments 2a and 2b), in conditioned hyperactivity and behavioral sensitization after a single methamphetamine injection in male, Swiss Webster mice. Mice received either a single injection (intraperitoneal, i.p.) of physiological saline (vehicle) or methamphetamine (2.0 mg/kg) prior to a 30-minute locomotor activity session (Conditioning). Tests for conditioned hyperactivity (CR Test) and behavioral sensitization (Methamphetamine Challenge Test) occurred after a delay of 2 and 3 days (Immediate), 6 and 7 days (Short), 14 and 15 days (Moderate), or 27 and 28 days (Long), respectively. To assess the role of catecholaminergic activity, specifically dopamine D2 receptors (Experiments 2a) or β-adrenergic receptors (Experiment 2b) on memory consolidation, and its subsequent effect of conditioned hyperactivity and behavioral sensitization, the dopamine D2 antagonist, haloperidol (40 μg/kg), or the non-selective β-adrenergic (β1/β2) antagonist, propranolol (16 and 32 mg/kg), was administered immediately or 2.5 h after methamphetamine conditioning. Conditioned hyperactivity and behavioral sensitization were detected at all time points (Experiment 1). Furthermore, post-conditioning administration of haloperidol or propranolol failed to alter conditioned hyperactivity or behavioral sensitization (Experiment 2a and 2b). Collectively, these results suggest that the 1) conditioned and pharmacological responses persisted unchanged for equal durations, and 2) targeting the catecholaminergic system during memory consolidation did not disrupt induction of either conditioning hyperactivity or sensitization.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174129"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506319","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}

{"title":"EGR1-mediated repression of HDAC2 regulates BDNF-dependent kindling development in a mouse model of pentylenetetrazol-induced epilepsy","authors":"Daisuke Ibi ,&nbsp;Keisuke Ishida ,&nbsp;Takaaki Kojima ,&nbsp;Shuri Yoshida ,&nbsp;Anna Suzuki ,&nbsp;Serina Suzuki ,&nbsp;Mai Yasui ,&nbsp;Kotarou Shibuya ,&nbsp;Moe Nakanishi ,&nbsp;Tomoe Yamagami ,&nbsp;Justin M. Saunders ,&nbsp;Mario de la Fuente Revenga ,&nbsp;Javier Gonzalez-Maeso ,&nbsp;Masayuki Hiramatsu","doi":"10.1016/j.pbb.2025.174131","DOIUrl":"10.1016/j.pbb.2025.174131","url":null,"abstract":"<div><div>Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Recent studies have reported altered expression of early growth response 1 (<em>Egr1</em>), an activity-inducible immediate early gene, and histone deacetylase 2 (HDAC2), a regulator of gene transcription through the removal of acetyl groups from histone tails, in the hippocampus of epilepsy patients and animal models. Here, we investigated the roles of EGR1 and HDAC2 in pentylenetetrazol (PTZ)-induced seizures in kindled mice. Chronic PTZ treatment increased EGR1 and decreased HDAC2 expression in the hippocampus. Furthermore, EGR1 bound to the <em>Hdac2</em> promoter and repressed its activity, but it had no effect when the predicted EGR1 binding site was deleted. Subsequently, we investigated the role of the HDAC2 in chemically induced kindling in mice with <em>Hdac2</em> deletion. <em>Hdac2</em> deletion suppressed PTZ-induced kindled seizures in mice compared with control mice. The upregulation of brain-derived neurotrophic factor (BDNF), a neurotrophin crucial for brain development, was observed in the hippocampi of control mice chronically treated with PTZ, but this increase was absent in mice with <em>Hdac2</em> deletion. Additionally, continuous microinjection of recombinant BDNF protein into the ventricle accelerated kindling in mice with <em>Hdac2</em> deletion, suggesting that HDAC2 contributes to the development of kindled seizures by regulating BDNF expression. In summary, HDAC2, which is negatively regulated by EGR1, induces BDNF expression in the hippocampus of PTZ-treated mice, resulting in the development of kindled seizures. These findings indicate that the EGR1-HDAC2-BDNF molecular pathway may serve as a therapeutic target in epilepsy.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174131"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557349","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}

{"title":"Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects","authors":"Lisa Katharina Ruoff ,&nbsp;Irina Wanda Helene Bänfer ,&nbsp;Djavid Elias Liedtke ,&nbsp;Sofie Elena China ,&nbsp;Jens Wiltfang ,&nbsp;Thomas A. Bayer ,&nbsp;Sören Frederik Bock ,&nbsp;Friederike Spandau ,&nbsp;Caroline Bouter ,&nbsp;Nicola Beindorff ,&nbsp;Yvonne Bouter","doi":"10.1016/j.pbb.2025.174127","DOIUrl":"10.1016/j.pbb.2025.174127","url":null,"abstract":"<div><h3>Background</h3><div>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.</div></div><div><h3>Aims</h3><div>This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.</div></div><div><h3>Methods</h3><div>Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, ¹⁸F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.</div></div><div><h3>Results</h3><div>Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.</div></div><div><h3>Conclusion</h3><div>Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174127"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496370","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}

{"title":"1,4-Naphthoquinone improves depressive-like behaviors by modulating neuronal factors and neuroinflammatory mediators","authors":"Joo Hye Sim ,&nbsp;Hye Jin Choi ,&nbsp;Ohhyeon Kwon ,&nbsp;Taeyeon Kim ,&nbsp;Doheon Lee ,&nbsp;Jeong June Choi","doi":"10.1016/j.pbb.2025.174133","DOIUrl":"10.1016/j.pbb.2025.174133","url":null,"abstract":"<div><div>Depression is a chronic mental disorder characterized by alternations in emotions, thoughts, physical condition, and behavior. Using the natural product database Compound Combination-Oriented Natural Product Database with Unified Terminology (COCONUT) and the bioinformatics tool CODA (Context-Oriented Directed Associations), we screened and identified 1,4-naphthoquinone (1,4-NQ) as a promising candidate for depression treatment. Oral administration of 1,4-NQ attenuated the depressive-like behaviors in the open field test (OFT), elevated plus maze test (EPM) and forced swim test (FST) in a chronic restraint stress (CRS)-induced depressive-like mouse model. Real-time PCR analysis demonstrated that 1,4-NQ increased the mRNA levels of 5-HT1A and BDNF in the hippocampus of mouse brains. The expression level of glucocorticoid receptor (GR) in the hippocampus was increased by 1,4-NQ treatment in both CRS- and corticosterone-induced depression mouse models. We confirmed that 1,4-NQ has anti-neuroinflammatory efficacy by suppressing the levels of IL-6, TNF-α and IL-1β in LPS-stimulated BV2 microglial cell line. The western blot and real-time PCR analysis demonstrated that 1,4-NQ increased the level of GR in both the U-138 MG glial cell line and the SH-SY5Y neuronal cell line. In conclusion, 1,4-NQ is supposed to have anti-depressive efficacy by alleviating depressive-like behaviors through modulation of neuroinflammatory mediators and GR expression in the nervous system.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174133"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582441","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}

{"title":"Adolescent stress differentially modulates the affective, psychomotor, and neural responses to a first amphetamine exposure in male Wistar rats","authors":"Andrey Sequeira-Cordero ,&nbsp;Juan C. Brenes","doi":"10.1016/j.pbb.2025.174126","DOIUrl":"10.1016/j.pbb.2025.174126","url":null,"abstract":"<div><div>The initial neurobehavioral adaptations following the first drug exposure may underlie the transition from recreational to compulsive use in vulnerable individuals. Compelling evidence indicates that early life adversity (ELA) is a significant risk factor for drug dependence. To better understand the relationship between ELA and initial drug experiences, we investigated whether chronic unpredictable stress (CUS) during adolescence modifies the affective (ultrasonic vocalizations, USVs), psychomotor (rearing and locomotion), and neural responses to a single dose of amphetamine in rats. CUS alone led to open-field hyperactivity and reduced flat USVs. CUS significantly blunted amphetamine-induced hyperactivity –suggesting a cross-tolerance effect– while it augmented amphetamine-induced appetitive 50-kHz calls, indicating a cross-sensitization effect. These results might suggest that CUS increases the rewarding and reduces the anxiogenic properties of initial amphetamine experience. At the neural level, amphetamine increased the expression of corticotropin-releasing factor (<em>Crf</em>)-related genes and the 2B subunit of the <em>N</em>-methyl-<span>d</span>-aspartate glutamate receptor (<em>Nr2b</em>) in a region-dependent manner. CUS upregulated the expression of brain-derived neurotrophic factor (<em>Bdnf</em>) in the medial prefrontal cortex (mPFC) and actin-related protein 2 (<em>Arp2</em>) in the nucleus accumbens (NAc). A cross-tolerance effect was observed for <em>Bdnf</em>, tropomyosin receptor kinase B (<em>TrkB</em>), and <em>Cofilin-1</em> in the mPFC. Conversely, the expression of Rho GTPase-activating protein 32 (<em>P250gap</em>), cAMP-response element binding protein (<em>Creb</em>), and DNA methyltransferase 3A (<em>Dnmt3a</em>) was cross-sensitized in the NAc. The coexistence of cross-sensitization and cross-tolerance neurobehavioral effects between CUS and amphetamine supports the idea that ELA can simultaneously blunt and heighten different brain substrates, collectively increasing the risk of drug dependence.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174126"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145471597","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}

{"title":"Combination treatment with medium dose THC and CBD had no therapeutic effect in a transgenic mouse model for Alzheimer's disease but affected other domains including anxiety-related behaviours and object recognition memory","authors":"Beate Aumer ,&nbsp;Rossana Rosa Porto ,&nbsp;Madilyn Coles ,&nbsp;Nina Ulmer ,&nbsp;Georgia Watt ,&nbsp;Heike Kielstein ,&nbsp;Tim Karl","doi":"10.1016/j.pbb.2025.174101","DOIUrl":"10.1016/j.pbb.2025.174101","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegenerative disease that effects memory and behaviour. The phytocannabinoid cannabidiol (CBD) has been found to reverse impairments of recognition as well as spatial memory deficits of AD transgenic mice but had only limited effects on disease-relevant brain pathologies. Recent evidence suggests that combining CBD with other cannabinoids including delta-9-tetrahydrocannabinol (THC) may lead to improved therapeutic outcomes. Thus, this study evaluated the chronic effects of combined treatment with 3 mg/kg THC and 20 mg/kg CBD on 14.5-month-old <em>APP</em>_<em>Swe</em><em>/PS1ΔE9</em> (<em>APP/PS1</em>) transgenic females and control littermates. Mice were treated with THCxCBD or vehicle (VEH) daily via intraperitoneal injections for 3 weeks before behavioural testing commenced. AD-relevant behavioural domains were analysed utilising Elevated Plus Maze (EPM), open field (OF), novel object recognition test (NORT), social interaction (SI), Y-maze (YM), and prepulse inhibition test (PPI). <em>APP/PS1</em> females showed an anxiety-like phenotype and object recognition deficits that remained unchanged by cannabinoid treatment. Interestingly, some effects of THCxCBD appeared genotype-dependent with cannabinoid treatment causing an anxiogenic EPM response in <em>APP/PS1</em> mice but having an anxiolytic-like effect in WT females. Moreover, THCxCBD administration disrupted the novel object preference of control females. Noteworthy, THCxCBD significantly decreased different fat depots and bodyweight of all mice across genotype. No other differences between genotypes or treatment groups were detected. In conclusion, the particular cannabinoid combination strategy utilised had no prominent therapeutic-like effect in 14.5-month-old <em>APP/PS1</em> females.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174101"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113968","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}

{"title":"Zebrafish models: Charting promising platform and illuminating the depths of depression","authors":"Binqi Yang ,&nbsp;Yu Han ,&nbsp;Yuanjing Yang ,&nbsp;Li Yuan ,&nbsp;Xiaopeng Zhu","doi":"10.1016/j.pbb.2025.174097","DOIUrl":"10.1016/j.pbb.2025.174097","url":null,"abstract":"<div><div>Depression, a prevalent mental disorder with significant global health implications, remains a complex and multifaceted challenge. Despite extensive research using traditional animal models and clinical trials, the underlying mechanisms of depression remain incompletely understood, hindering the development of effective treatments. Zebrafish (<em>Danio rerio</em>), with their remarkable genetic and neurobiological similarities to humans, have emerged as a powerful tool for investigating the complexities of depression. Zebrafish exhibit a rich and quantifiable behavioral repertoire, with assays such as the novel tank test, light–dark box, open field, shoaling, maze test, and tail immobilization used to assess depression-like phenotypes. Diverse modeling approaches (including genetic and pharmacological manipulations, chronic stress paradigms, and gut–brain axis studies) have been applied, enabling investigations into the physiological, genetic, pharmacological, and environmental drivers of depression. The integration of zebrafish into depression research offers unique opportunities to advance mechanistic insight and accelerate antidepressant discovery. This review summarizes recent progress, examines current challenges, and outlines future directions to maximize the translational potential of zebrafish depression models.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174097"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086850","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}

{"title":"From morphine to buprenorphine - Modeling opioid use disorder and its treatment during pregnancy: Effects on maternal care and offspring neurodevelopment in a translational rodent model","authors":"Lauren M. Richardson ,&nbsp;Abigail M. Myers ,&nbsp;Jecenia Duran ,&nbsp;Deep K. Patel ,&nbsp;Kit L. Tran ,&nbsp;Ella R. Walsh ,&nbsp;Shane A. Perrine ,&nbsp;Scott E. Bowen ,&nbsp;Susanne Brummelte","doi":"10.1016/j.pbb.2025.174112","DOIUrl":"10.1016/j.pbb.2025.174112","url":null,"abstract":"<div><div>Opioid use during pregnancy has increased drastically in the last two decades. Pregnant women who use opioids are often prescribed Medications for Opioid Use Disorder (MOUDs), including buprenorphine (BUP), to mitigate negative effects on the fetus. However, BUP exposure during pregnancy may still negatively impact maternal care behavior and offspring neurodevelopment. In the current study, we used a translational rodent model to investigate the effects of continued morphine or BUP use from preconception (7 days prior to mating) to the early postpartum period, as well as the transition from morphine to BUP during early pregnancy (gestational day (GD) 5), on both maternal care behaviors and acute offspring neurodevelopmental outcomes. Our results reveal that exposure to BUP beginning before pregnancy or on GD5 resulted in decreased nesting quality, maternal motivation, and pup-directed care behaviors as compared to controls. For the offspring, BUP-exposure resulted in increased pup mortality, more neonatal opioid withdrawal syndrome-like (NOWS) symptoms, altered norepinephrine levels in the brain, and decreased offspring weight, body length, and presence of milk bands compared to vehicle pups. Importantly, maternal care behavior was significantly correlated with offspring mortality, physical maturation, and NOWS-like scores, suggesting that at least some of the adverse effects were driven by impairments in maternal care. Morphine-exposed dams and pups showed overall fewer impairments compared to BUP-exposed dams and pups. This highlights that more research is needed to further understand the unique impact of BUP on the maternal brain and subsequent infant outcomes to mitigate potential adverse effects in pregnant women with MOUD prescriptions.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174112"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258850","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}

{"title":"Autophagy activation ameliorates cognitive deficits and alpha-synuclein pathology in an adeno-associated viral vector mediated rat model of Lewy body disorders","authors":"Elif Cinar ,&nbsp;Gül Yalcin-Cakmakli ,&nbsp;Hilal Akyel ,&nbsp;Ayse Ulusoy ,&nbsp;Banu Cahide Tel ,&nbsp;Bülent Elibol","doi":"10.1016/j.pbb.2025.174096","DOIUrl":"10.1016/j.pbb.2025.174096","url":null,"abstract":"<div><div>Lewy body disorders (LBD), including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by the aggregation of alpha-synuclein (a-syn). Despite shared pathological features, these disorders have distinct clinical characteristics, in terms of both motor and cognitive symptoms.</div><div>We created a unique rat model of dual-site injection of adeno-associated viral vectors carrying human a-syn (AAV5-h-a-syn) simultaneously and bilaterally into the substantia nigra and dentate gyrus, to recapitulate both nigrostriatal and hippocampal-based a-syn pathology associated with PDD and DLB. Inspired by the distinct pathological features of the model, namely the CA2-dominated accumulation of phosphorylated a-syn, in the current study we aimed to evaluate comparatively the consequences of autophagic induction on a-syn pathology in these targeted areas. This was achieved by the chronic administration of rapamycin, for 8 weeks starting 10 weeks post-AAV injections. Behavioral assessments were conducted by evaluation of locomotor activity, anxiety-related behavior, object and spatial learning and memory. Histopathological examinations involved in-depth analysis of a-syn pathology, neuronal and synaptic integrity and autophagic markers.</div><div>Results demonstrated that rapamycin significantly ameliorated cognitive deficits and reduced phosphorylated a-syn accumulation, significantly in CA2 throughout all its sublayers and partially in CA3 sublayers. Despite no alteration in NeuN and TH levels, synaptophysin expressions were decreased in both the hippocampus and striatum in a-syn overexpressing animals, which were partially restored by rapamycin treatment. Intriguingly, autophagic activation, as indicated by the increased expression of beclin-1, LC3-I/II, p62, and Atg proteins, was predominantly observed in the hippocampus but not in the striatum, suggesting region-specific differential response to autophagic induction in terms of a-syn pathology.</div><div>This dual-site injection model provides a valuable tool for studying a-syn-related dementia and evaluating potential restorative therapies. Our findings underscore the importance of autophagy-targeting early interventions to alleviate cognitive deficits by reducing hippocampal a-syn burden in LBD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174096"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054945","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}

{"title":"Creatine prevents ouabain-induced manic-like behavior by modulating GSK-3β via PI3K/AKT/mTOR pathway","authors":"Adson Souza-Pereira ,&nbsp;Jozyê Milena da Silva Guerra ,&nbsp;Bruno Henrique Nieswald ,&nbsp;Luan Machado Maidana ,&nbsp;Amistron Benites Correa ,&nbsp;Douglas Buchmann Godinho ,&nbsp;Luiz Fernando Freire Royes ,&nbsp;Leonardo Magno Rambo","doi":"10.1016/j.pbb.2025.174115","DOIUrl":"10.1016/j.pbb.2025.174115","url":null,"abstract":"<div><div>Bipolar disorder is a chronic psychiatric condition marked by alternating episodes of mania and depression. Current pharmacological treatments show limited efficacy and are often associated with incomplete remission. Creatine, a compound involved in energy buffering, mitochondrial function, and neuromodulation, has demonstrated neuroprotective and potential mood-stabilizing properties. However, the underlying mechanisms remain poorly understood. This study evaluated the effects of acute oral creatine administration (300 mg/kg) on behavioral and molecular changes in a validated rat model of mania induced by intracerebroventricular ouabain (10⁻³ M), a Na⁺/K⁺-ATPase inhibitor. Behavioral alterations were assessed using the open field test, and hippocampal samples were analyzed for enzyme activity and key signaling proteins. Creatine significantly attenuated ouabain-induced hyperactivity and increased latency to symptom onset. At the molecular level, creatine preserved Na⁺/K⁺-ATPase activity and reduced phosphorylation of its α-subunit at a regulatory site. Additionally, creatine enhanced activation of the PI3K/AKT/mTOR/p70S6K pathway and prevented the ouabain-induced activation of GSK-3β, a kinase involved in mood regulation. Notably, rapamycin, an mTOR inhibitor, reversed the behavioral effects of creatine, suggesting a mechanistic role for this pathway. These findings demonstrate that acute creatine administration confers both behavioral and neurochemical protection in a mania model and supports its potential as an adjunctive therapeutic strategy for individuals with bipolar disorder.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174115"},"PeriodicalIF":2.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280927","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}