Pharmacology Biochemistry and Behavior最新文献

{"title":"Creatine prevents ouabain-induced manic-like behavior by modulating GSK-3β via PI3K/AKT/mTOR pathway.","authors":"Adson de Souza Pereira, Jozyê Milena da Silva Guerra, Bruno Henrique Nieswald, Luan Machado Maidana, Amistron Benites Correa, Douglas Buchmann Godinho, Luiz Fernando Freire Royes, Leonardo Magno Rambo","doi":"10.1016/j.pbb.2025.174115","DOIUrl":"https://doi.org/10.1016/j.pbb.2025.174115","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":" ","pages":"174115"},"PeriodicalIF":2.5,"publicationDate":"2025-10-10","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}

{"title":"Sex differences in acute tolerance to the objective and subjective effects of alcohol","authors":"Annie K. Griffith,&nbsp;Mark T. Fillmore","doi":"10.1016/j.pbb.2025.174111","DOIUrl":"10.1016/j.pbb.2025.174111","url":null,"abstract":"<div><div>Alcohol is well known for impairing motor coordination and increasing subjective intoxication. Previous research has found that these effects are exacerbated in women, but such observations were limited to times when blood alcohol concentrations (BACs) were at or near peak. Interestingly, alcohol-induced impairment of motor coordination and subjective intoxication both demonstrate acute tolerance, meaning they recover faster than the decline of BAC as alcohol is eliminated. Consideration of acute tolerance to both measures in tandem is particularly important because if recovery from subjective intoxication outpaces recovery from objective motor impairment, a drinker may develop a false sense of freedom from the impairing effects of alcohol. Such a misjudgment can lead the drinker to engage in risky behavior as BAC declines. The present study examined whether sex differences were present in the acute tolerance to motor impairment and subjective intoxication. Twenty-five women and 25 men participated in a placebo-controlled study of their acute tolerance to motor impairment and subjective intoxication following a moderate dose of alcohol, 0.60 g/kg for women and 0.64 g/kg for men. Repeated assessments of motor coordination with a grooved pegboard and subjective intoxication with a visual analog scale were conducted seven times as BAC declined. While all participants demonstrated acute tolerance to both motor impairment and subjective intoxication, women exhibited significantly faster recovery from subjective intoxication than men. Consequently, women may be more likely than men to engage in risky behavior on the descending limb, such as alcohol-impaired driving.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174111"},"PeriodicalIF":2.5,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258796","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, Abigail M Myers, Jecenia Duran, Deep K Patel, Kit L Tran, Ella R Walsh, Shane A Perrine, Scott E Bowen, Susanne Brummelte","doi":"10.1016/j.pbb.2025.174112","DOIUrl":"https://doi.org/10.1016/j.pbb.2025.174112","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":" ","pages":"174112"},"PeriodicalIF":2.5,"publicationDate":"2025-10-07","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":"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, Rossana Rosa-Porto, Madilyn Coles, Nina Ulmer, Georgia Watt, Heike Kielstein, Tim Karl","doi":"10.1016/j.pbb.2025.174101","DOIUrl":"https://doi.org/10.1016/j.pbb.2025.174101","url":null,"abstract":"<p><p>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 APP_Swe/PS1ΔE9 (APP/PS1) 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). APP/PS1 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 APP/PS1 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 APP/PS1 females.</p>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":" ","pages":"174101"},"PeriodicalIF":2.5,"publicationDate":"2025-09-19","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":"Nicotine e-cigarette exposure in utero diminishes spatial memory and has negative effects on attention in a dose-, diet- and sex-dependent manner.","authors":"Nicole M. Roeder ,&nbsp;Samantha L. Penman ,&nbsp;Brittany J. Richardson ,&nbsp;Jia Wang ,&nbsp;Lily Freeman-Striegel ,&nbsp;Ojas Pareek ,&nbsp;Rina Eiden ,&nbsp;Saptarshi Chakraborty ,&nbsp;Panayotis K. Thanos","doi":"10.1016/j.pbb.2025.174102","DOIUrl":"10.1016/j.pbb.2025.174102","url":null,"abstract":"<div><h3>Rationale</h3><div>Clinical and preclinical literature has linked prenatal nicotine exposure to several cognitive effects, including memory and attentional deficits. However, many preclinical studies focus on effects during adulthood and do not use clinically relevant nicotine delivery system.</div></div><div><h3>Objective</h3><div>Our study aims to examine the impact of prenatal nicotine exposure on cognition in adolescents using an inhalation model to mimic e-cigarette exposure.</div></div><div><h3>Methods</h3><div>Pregnant rats were exposed to either air, 24 mg/mL nicotine (low-dose nicotine, LDNIC), or 59 mg/mL nicotine (high-dose nicotine, HDNIC). Inhalations were conducted daily from 0900 to 1100. Offspring from each of the treatment groups were provided with a normal diet (ND) or high-fat diet (HFD). Novel object recognition (NOR), Morris water maze (MWM), and object-based attention (OBA) testing were conducted during early (PND 24-30) and late-adolescent (PND 44-51) periods.</div></div><div><h3>Results</h3><div>NOR indicated that prenatal HDNIC rats spent significantly less time exploring objects compared to air controls. Altered exploratory behavior was also observed in OBA in a dose-dependent manner. HDNIC ND rats also displayed signs of memory deficit, and this was seen most robustly in HDNIC ND female rats, with no observed effects in the HFD group.</div></div><div><h3>Conclusions</h3><div>Overall, our study indicates that prenatal vaporized nicotine exposure negatively affects spatial memory and appears to diminish performance in attention-related tasks, while HFD seems to protect from these negative effects.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174102"},"PeriodicalIF":2.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109034","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":"Locomotor stimulant and drug discrimination effects of five synthetic cathinones in rodents","authors":"Michael B. Gatch,&nbsp;Rebecca Darbi Hill,&nbsp;Ritu A. Shetty,&nbsp;Nana Kofi Kusi-Boadum,&nbsp;Jeanne Priddy,&nbsp;Nathalie Sumien,&nbsp;Michael J. Forster","doi":"10.1016/j.pbb.2025.174100","DOIUrl":"10.1016/j.pbb.2025.174100","url":null,"abstract":"<div><div>Synthetic cathinones are synthesized as legal alternatives to methamphetamine, cocaine and MDMA, and can produce serious health risks. The DEA identified five synthetic cathinones of interest: N-ethylpentedrone, N-ethylheptedrone, N-butylhexedrone, 4-methylpentedrone, and 4-methyl-α-ethylaminopentiophenone (4-MEAP). These compounds were tested to determine their locomotor stimulant and psychostimulant-like discriminative stimulus effects. Locomotor activity was tested in male Swiss-Webster mice to identify behaviorally active dose ranges and time courses. Discriminative stimulus effects of the five synthetic cathinones were tested in male Sprague-Dawley rats trained to discriminate cocaine (10 mg/kg, 10-min pretreatment) or methamphetamine (1 mg/kg, 10-min pretreatment) from saline vehicle. Four of the test compounds produced locomotor stimulant effects comparable in efficacy to methamphetamine and cocaine, with rank order of potency: 4-MEAP &gt; N-ethylpentedrone &gt; N-ethylheptedrone &gt;4-methyl-pentedrone. N-butylhexedrone depressed locomotor activity. N-Ethylpentedrone and N-ethylheptedrone substituted for the discriminative stimulus effects produced by methamphetamine and cocaine. 4-MEAP fully substituted for methamphetamine. 4-Methylpentedrone fully substituted for cocaine, but only partially substituted for methamphetamine, while N-butylhexedrone partially substituted for cocaine in DD and failed to substitute for methamphetamine. Three of the compounds, N-ethylpentedrone, N-ethylheptedrone, and 4-MEAP produced robust psychostimulant-like effects, which suggests they will have abuse liability similar to cocaine or methamphetamine. 4-Methylpentedrone was a slow onset locomotor stimulant, and substituted for cocaine and only partially substituted for methamphetamine, which may indicate a weaker abuse liability compared to methamphetamine or cocaine. N-butylhexedrone produced weak psychostimulant-like effects, which suggests it may have limited use as a street drug on its own.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174100"},"PeriodicalIF":2.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102742","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":"2025-09-16","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":"Advancements in psychedelic research: Effects, mechanisms, and therapeutic potential as emerging antidepressants","authors":"Xian-Qiang Zhang ,&nbsp;De-Nong Liu ,&nbsp;Qing-Shan Miao ,&nbsp;Xu Cai ,&nbsp;Lu-Xin Zong ,&nbsp;Yu-Kun Hou ,&nbsp;Jing Xiong","doi":"10.1016/j.pbb.2025.174099","DOIUrl":"10.1016/j.pbb.2025.174099","url":null,"abstract":"<div><div>Major depressive disorder (MDD) causes great physical and mental suffering to patients while also imposing a tremendous economic burden on the global economy. Psychedelics, also known as serotonergic hallucinogens, are potent psychoactive compounds known for their ability to alter mood, perception, and a range of cognitive functions. Increasing evidence suggests that some psychedelics positively facilitate individual social functions, with rapid and sustained improvement in symptoms associated with MDD. Consequently, the application of psychedelics in the treatment of MDD has garnered considerable attention from researchers in recent years. This review examines recent advancements in evaluating the behavioral and physiological effects of psychedelics in both preclinical animal models and clinical trials focused on MDD. Additionally, we summarize and discuss the cellular, brain region, and circuit-level mechanisms, as well as potential intracellular signaling pathways, that may contribute to the antidepressant effects of psychedelics. Based on current evidence, we conclude that psychedelics hold significant promise as therapeutic agents for MDD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174099"},"PeriodicalIF":2.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065110","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":"Kisspeptin-13 induces hyperalgesia and modulates the expression of opioid and glutamate receptors in mice","authors":"Éva Bodnár,&nbsp;Katalin Eszter Ibos,&nbsp;Kata Filkor,&nbsp;Krisztina Csabafi","doi":"10.1016/j.pbb.2025.174098","DOIUrl":"10.1016/j.pbb.2025.174098","url":null,"abstract":"<div><div>Kisspeptins are hypothalamic neuropeptides well known for their role in reproductive biology. Our previous results have demonstrated that kisspeptin-13 (KP-13) has pronociceptive and anti-opioid effects. In our present experiments, we investigated the effects of KP-13 on nociception under both physiological and inflammatory conditions, as well as on the gene expression of regions involved in mediating pain sensation in C57BL/6 mice.</div><div>Different doses of KP-13 were administered to adult male C57BL/6 mice, and either the tail-flick latency was measured in the tail-flick test or the time spent with nocifensive behavior was determined in the formalin test. In another group of animals, after KP-13 treatment, qPCR was used to determine the relative gene expression of <em>Oprd1</em>, <em>Oprk1</em>, <em>Oprm1</em>, <em>Grin1</em>, <em>Grin2b</em>, <em>Grin2d</em>, and <em>Grm5</em> in samples of the dorsal root ganglion (DRG), amygdala, hypothalamus, and anterior cingulate cortex (ACC).</div><div>Our results showed that KP-13 treatment decreased the tail-flick latency in a dose-dependent manner. In the formalin test, the KP-13-treated group showed increased nocifensive behavior compared to the control group. In DRG, KP-13 caused upregulation of <em>Oprd1</em> and downregulation of <em>Oprk1</em>. In the amygdala, KP-13 decreased the expression of <em>Oprd1</em> and <em>Grin2b</em>. In the hypothalamus, both <em>Oprm1</em> and <em>Oprd1</em> were downregulated. In the ACC, <em>Oprk1</em> and <em>Grm5</em> expression increased, whereas a decrease in <em>Grin2b</em> expression was observed.</div><div>In conclusion, our results suggest that KP-13 has a hyperalgesic effect, which may be mediated by region-specific alterations in the gene expression of opioid and glutamate receptors.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174098"},"PeriodicalIF":2.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054971","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":"2025-09-10","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}