Pub Date : 2025-11-10DOI: 10.1016/j.pbb.2025.174128
Agata Siwek , Monika Marcinkowska , Barbara Mordyl , Monika Głuch-Lutwin , Małgorzata Wolak , Magdalena Jastrzębska-Więsek , Natalia Wilczyńska-Zawal , Elżbieta Wyska , Katarzyna Szafrańska , Anna Wesołowska , Marcin Kołaczkowski
In addition to cognitive decline, 90 % of dementia patients experience behavioral and psychological symptoms of dementia, for which no safe and effective pharmacotherapy currently exists. Our study aimed to determine the therapeutic potential of the new dual 5-HT6/SERT-acting ligand MM394 in the context of pro-cognitive and neuroprotective properties, as well as its effects on behavioral symptoms and mood disorders in patients diagnosed with Alzheimer's disease. We performed in vitro experiments to examine the neuroprotective and antioxidant properties of MM394, as well as in vivo studies on male rats to evaluate its pharmacokinetics and potential in behavioral modulation of memory and mood. Following this, we attempted to determine the molecular mechanism of action of the dual 5-HT6/SERT targeting compound in ex vivo experiments using rats' hippocampus and prefrontal cortex. The results of our study in the HT-22 cell line support the potential of MM394 to target excitotoxicity and oxidative stress, which play a key role in neurodegeneration. Furthermore, the compound exhibits antidepressant-like activity in the forced swim test and counteracts the memory impairments caused by MK-801 in the novel object recognition assessment in rats. Ex vivo findings demonstrate that MM394 modulates mTOR and ERK1/2 phosphorylation in the studied brain areas and increases the level of BDNF in the hippocampus when co-administered with MK-801 in the novel object recognition test. As a result of these findings, MM394 may be useful as a therapeutic for BPSD, which should be further explored.
{"title":"Simultaneous modulation of 5-HT6 and SERT by MM394: a dual-target ligand providing neuroprotection against amyloid-β toxicity, memory preservation, and alleviation of BPSD symptoms","authors":"Agata Siwek , Monika Marcinkowska , Barbara Mordyl , Monika Głuch-Lutwin , Małgorzata Wolak , Magdalena Jastrzębska-Więsek , Natalia Wilczyńska-Zawal , Elżbieta Wyska , Katarzyna Szafrańska , Anna Wesołowska , Marcin Kołaczkowski","doi":"10.1016/j.pbb.2025.174128","DOIUrl":"10.1016/j.pbb.2025.174128","url":null,"abstract":"<div><div>In addition to cognitive decline, 90 % of dementia patients experience behavioral and psychological symptoms of dementia, for which no safe and effective pharmacotherapy currently exists. Our study aimed to determine the therapeutic potential of the new dual 5-HT<sub>6</sub>/SERT-acting ligand MM394 in the context of pro-cognitive and neuroprotective properties, as well as its effects on behavioral symptoms and mood disorders in patients diagnosed with Alzheimer's disease. We performed <em>in vitro</em> experiments to examine the neuroprotective and antioxidant properties of MM394, as well as <em>in vivo</em> studies on male rats to evaluate its pharmacokinetics and potential in behavioral modulation of memory and mood. Following this, we attempted to determine the molecular mechanism of action of the dual 5-HT<sub>6</sub>/SERT targeting compound in <em>ex vivo</em> experiments using rats' hippocampus and prefrontal cortex. The results of our study in the HT-22 cell line support the potential of MM394 to target excitotoxicity and oxidative stress, which play a key role in neurodegeneration. Furthermore, the compound exhibits antidepressant-like activity in the forced swim test and counteracts the memory impairments caused by MK-801 in the novel object recognition assessment in rats. <em>Ex vivo</em> findings demonstrate that MM394 modulates mTOR and ERK1/2 phosphorylation in the studied brain areas and increases the level of BDNF in the hippocampus when co-administered with MK-801 in the novel object recognition test. As a result of these findings, MM394 may be useful as a therapeutic for BPSD, which should be further explored.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174128"},"PeriodicalIF":2.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145506304","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 : 2025-11-09DOI: 10.1016/j.pbb.2025.174127
Lisa Katharina Ruoff , Irina Wanda Helene Bänfer , Djavid Elias Liedtke , Sofie Elena China , Jens Wiltfang , Thomas A. Bayer , Sören Frederik Bock , Friederike Spandau , Caroline Bouter , Nicola Beindorff , Yvonne Bouter
Background
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.
Aims
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.
Methods
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.
Results
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.
Conclusion
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.
{"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 , Irina Wanda Helene Bänfer , Djavid Elias Liedtke , Sofie Elena China , Jens Wiltfang , Thomas A. Bayer , Sören Frederik Bock , Friederike Spandau , Caroline Bouter , Nicola Beindorff , 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, <sup>18</sup>F-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":"2025-11-09","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}
Pub Date : 2025-11-05DOI: 10.1016/j.pbb.2025.174126
Andrey Sequeira-Cordero , Juan C. Brenes
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 (Crf)-related genes and the 2B subunit of the N-methyl-d-aspartate glutamate receptor (Nr2b) in a region-dependent manner. CUS upregulated the expression of brain-derived neurotrophic factor (Bdnf) in the medial prefrontal cortex (mPFC) and actin-related protein 2 (Arp2) in the nucleus accumbens (NAc). A cross-tolerance effect was observed for Bdnf, tropomyosin receptor kinase B (TrkB), and Cofilin-1 in the mPFC. Conversely, the expression of Rho GTPase-activating protein 32 (P250gap), cAMP-response element binding protein (Creb), and DNA methyltransferase 3A (Dnmt3a) 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.
{"title":"Adolescent stress differentially modulates the affective, psychomotor, and neural responses to a first amphetamine exposure in male Wistar rats","authors":"Andrey Sequeira-Cordero , 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":"2025-11-05","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}
Pub Date : 2025-10-24DOI: 10.1016/j.pbb.2025.174117
Shigeyuki Chaki , Yumiko Imadera
Although three dual orexin receptor antagonists (DORAs), suvorexant, lemborexant, and daridorexant, are currently available and widely used to treat insomnia, the differences in their elimination half-lives are not sufficient. As a result, clinicians have limited ability to tailor therapy to individual sleep complaints. The emergence of vornorexant, with a notably short half-life comparable to that of zolpidem, may substantially expand the clinical utility of DORAs. This broader spectrum of pharmacokinetic profiles enables more individualized treatment strategies that align with patients' specific sleep complaints. This approach, in turn, potentially reshapes the therapeutic paradigm of insomnia management. However, several challenges remain to be addressed in order to fully realize the clinical potential of DORAs. This review identifies four key challenges requiring resolution to advance their optimal use in clinical practice.
{"title":"Dual orexin receptor antagonists in insomnia: Toward a new therapeutic paradigm","authors":"Shigeyuki Chaki , Yumiko Imadera","doi":"10.1016/j.pbb.2025.174117","DOIUrl":"10.1016/j.pbb.2025.174117","url":null,"abstract":"<div><div>Although three dual orexin receptor antagonists (DORAs), suvorexant, lemborexant, and daridorexant, are currently available and widely used to treat insomnia, the differences in their elimination half-lives are not sufficient. As a result, clinicians have limited ability to tailor therapy to individual sleep complaints. The emergence of vornorexant, with a notably short half-life comparable to that of zolpidem, may substantially expand the clinical utility of DORAs. This broader spectrum of pharmacokinetic profiles enables more individualized treatment strategies that align with patients' specific sleep complaints. This approach, in turn, potentially reshapes the therapeutic paradigm of insomnia management. However, several challenges remain to be addressed in order to fully realize the clinical potential of DORAs. This review identifies four key challenges requiring resolution to advance their optimal use in clinical practice.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174117"},"PeriodicalIF":2.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-15DOI: 10.1016/j.pbb.2025.174114
Wenfeng Hu , Minxiu Ye , Qijun Dai , Micona Sun , Rongrong Song , Xu Lu , Chao Huang , Lin Zhang , Rongrong Yang
Intranasal infusion of lymphocyte-activating gene-3 antibody (In-LAG3-Ab) has microglia-dependent antidepressant effects, but the underlying mechanism remains unclear. Since microglia can interact with astrocytes through purinergic signaling, we hypothesize that microglia-driven purinergic signaling may mediate the antidepressant effect of In-LAG3-Ab. The results showed that a single In-LAG3-Ab infusion in chronically stressed mice produced both an antidepressant effect and increased adenosine triphosphate (ATP) levels in the dentate gyrus, both of which were suppressed by chemogenetic inhibition of microglia in the dentate gyrus. Depletion of ATP or non-specific antagonism of purinergic receptors abolished the antidepressant effect of In-LAG3-Ab. Specific inhibition of purinergic 2Y1 receptors (P2Y1Rs), but not other purinergic receptors, in the hippocampus or conditional depletion of P2Y1Rs in astrocytes also abolished the antidepressant effect of In-LAG3-Ab. Brain-derived neurotrophic factor (BDNF) may act downstream of astrocytic P2Y1Rs to mediate the antidepressant effect of In-LAG3-Ab, as (i) chemogenetic inhibition of microglia in the dentate gyrus, specific deletion of astrocytic P2Y1Rs, and depletion of endogenous ATP abolished the reversal effect of In-LAG3-Ab on chronic stress-induced decreases in BDNF in the dentate gyrus, and (ii) infusion of BDNF-Ab into the hippocampus abolished the antidepressant effect of In-LAG3-Ab. These results suggest that astrocytic P2Y1R signaling associated with microglia stimulation may mediate the antidepressant effect of In-LAG3-Ab through BDNF.
{"title":"Intranasal LAG3 antibody infusion induces microglia-dependent antidepressant effect by mobilizing astrocytic P2Y1R-mediated BDNF synthesis in the hippocampus","authors":"Wenfeng Hu , Minxiu Ye , Qijun Dai , Micona Sun , Rongrong Song , Xu Lu , Chao Huang , Lin Zhang , Rongrong Yang","doi":"10.1016/j.pbb.2025.174114","DOIUrl":"10.1016/j.pbb.2025.174114","url":null,"abstract":"<div><div>Intranasal infusion of lymphocyte-activating gene-3 antibody (In-LAG3-Ab) has microglia-dependent antidepressant effects, but the underlying mechanism remains unclear. Since microglia can interact with astrocytes through purinergic signaling, we hypothesize that microglia-driven purinergic signaling may mediate the antidepressant effect of In-LAG3-Ab. The results showed that a single In-LAG3-Ab infusion in chronically stressed mice produced both an antidepressant effect and increased adenosine triphosphate (ATP) levels in the dentate gyrus, both of which were suppressed by chemogenetic inhibition of microglia in the dentate gyrus. Depletion of ATP or non-specific antagonism of purinergic receptors abolished the antidepressant effect of In-LAG3-Ab. Specific inhibition of purinergic 2Y1 receptors (P2Y1Rs), but not other purinergic receptors, in the hippocampus or conditional depletion of P2Y1Rs in astrocytes also abolished the antidepressant effect of In-LAG3-Ab. Brain-derived neurotrophic factor (BDNF) may act downstream of astrocytic P2Y1Rs to mediate the antidepressant effect of In-LAG3-Ab, as (i) chemogenetic inhibition of microglia in the dentate gyrus, specific deletion of astrocytic P2Y1Rs, and depletion of endogenous ATP abolished the reversal effect of In-LAG3-Ab on chronic stress-induced decreases in BDNF in the dentate gyrus, and (ii) infusion of BDNF-Ab into the hippocampus abolished the antidepressant effect of In-LAG3-Ab. These results suggest that astrocytic P2Y1R signaling associated with microglia stimulation may mediate the antidepressant effect of In-LAG3-Ab through BDNF.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174114"},"PeriodicalIF":2.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-13DOI: 10.1016/j.pbb.2025.174116
Didem Derici Yıldırım , Özge Selin Çevik , Erdal Horata , Coşar Uzun
Anxiety-like complex behavioral and psychological constructs are difficult to evaluate in rodents. Many studies have investigated which techniques are appropriate for measuring anxiety and related physiological parameters. Here, we used network meta-analysis to compare the current methods of assessing anxiety. We performed a comprehensive review and network meta-analysis by searching PubMed, EMBASE, the Cochrane Library, SCOPUS, and Web of Science for studies involving rodents with anxiety-related behaviors undergoing behavioral tests with certain keywords: The common parameters that emerged were total distance traveled, fecal boli count, and rearing behavior. In the 46 studies reviewed, the open-field test (OFT) and elevated plus maze (EPM) test appeared most often (in 45 and 43 studies, respectively), while the light–dark box (LDB) and elevated zero maze tests appeared less frequently (in two studies and one study, respectively Subsequently, the tests were ranked based on their likelihood of being the most effective measure for each outcome. For total distance traveled, the OFT showed a significant disadvantage over the EPM and LDB. For fecal boli, there was a significant difference between the LDB and OFT. There were no variations between tests in terms of rearing. Our findings reinforce the importance of considering each behavioral test's unique characteristics when selecting appropriate measures for anxiety-like behaviors. Researchers should exercise caution when interpreting single-measure outcomes and adopt a holistic approach that integrates multiple test results to achieve reliable and relevant conclusions. Network meta-analysis is a powerful tool for identifying the highlights, complexities, and inconsistencies of anxiety-related behaviors in rodents in preclinical anxiety models.
在啮齿类动物中，类似焦虑的复杂行为和心理结构难以评估。许多研究调查了哪些技术适合测量焦虑和相关的生理参数。在这里，我们使用网络元分析来比较目前评估焦虑的方法。我们通过检索PubMed、EMBASE、Cochrane图书馆、SCOPUS和Web of Science，对涉及焦虑相关行为的啮齿动物的研究进行了全面的回顾和网络荟萃分析，并对某些关键词进行了行为测试：出现的常见参数是总行走距离、粪便计数和饲养行为。在回顾的46项研究中，开放式测试（OFT）和高架迷宫（EPM）测试出现的频率最高（分别在45项和43项研究中），而光暗箱测试（LDB）和高架零迷宫测试出现的频率较低（分别在两项研究和一项研究中）。随后，根据它们对每个结果最有效的测量方法的可能性对这些测试进行了排名。对于总行驶距离，OFT比EPM和LDB表现出明显的劣势。对于粪肠，LDB和OFT之间存在显著差异。在饲养方式方面，试验之间没有差异。我们的研究结果强调了在选择合适的焦虑类行为测量方法时，考虑每个行为测试的独特特征的重要性。研究人员在解释单一测量结果时应谨慎行事，并采用综合多个测试结果的整体方法，以获得可靠和相关的结论。网络荟萃分析是识别临床前焦虑模型中啮齿动物焦虑相关行为的亮点、复杂性和不一致性的有力工具。
{"title":"Challenges in cross-test comparison of anxiety-related outcomes in rodents: A network meta-analysis","authors":"Didem Derici Yıldırım , Özge Selin Çevik , Erdal Horata , Coşar Uzun","doi":"10.1016/j.pbb.2025.174116","DOIUrl":"10.1016/j.pbb.2025.174116","url":null,"abstract":"<div><div>Anxiety-like complex behavioral and psychological constructs are difficult to evaluate in rodents. Many studies have investigated which techniques are appropriate for measuring anxiety and related physiological parameters. Here, we used network meta-analysis to compare the current methods of assessing anxiety. We performed a comprehensive review and network meta-analysis by searching PubMed, EMBASE, the Cochrane Library, SCOPUS, and Web of Science for studies involving rodents with anxiety-related behaviors undergoing behavioral tests with certain keywords: The common parameters that emerged were total distance traveled, fecal boli count, and rearing behavior. In the 46 studies reviewed, the open-field test (OFT) and elevated plus maze (EPM) test appeared most often (in 45 and 43 studies, respectively), while the light–dark box (LDB) and elevated zero maze tests appeared less frequently (in two studies and one study, respectively Subsequently, the tests were ranked based on their likelihood of being the most effective measure for each outcome. For total distance traveled, the OFT showed a significant disadvantage over the EPM and LDB. For fecal boli, there was a significant difference between the LDB and OFT. There were no variations between tests in terms of rearing. Our findings reinforce the importance of considering each behavioral test's unique characteristics when selecting appropriate measures for anxiety-like behaviors. Researchers should exercise caution when interpreting single-measure outcomes and adopt a holistic approach that integrates multiple test results to achieve reliable and relevant conclusions. Network meta-analysis is a powerful tool for identifying the highlights, complexities, and inconsistencies of anxiety-related behaviors in rodents in preclinical anxiety models.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174116"},"PeriodicalIF":2.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-12DOI: 10.1016/j.pbb.2025.174113
Mia I. Rough, Brianna F. Roberts, Michael A. Nader
Cocaine use disorder (CUD) remains a major public health challenge with no effective pharmacological treatments to date. Although extensive preclinical research using animal models has advanced our understanding, these findings have yet to translate into clinical success. This review highlights key independent variables that should be incorporated to improve the validity and translational relevance of animal studies. The discussion is organized around three primary domains: the agent; the host; and the environment. Most studies in this review focus on cocaine as the agent and host factors such as species and sex are emphasized as important independent variables influencing outcomes. The central theme of this review is to emphasize, from a preclinical model perspective, the critical role of environmental context, including operant conditioning parameters like schedules of reinforcement and maintaining events, as well as social housing conditions, which profoundly impact cocaine-maintained behavior and the effectiveness of interventions for cocaine self-administration.
{"title":"The impact of sex, species, environmental context, and alternative reinforcers in animal models of cocaine use disorders","authors":"Mia I. Rough, Brianna F. Roberts, Michael A. Nader","doi":"10.1016/j.pbb.2025.174113","DOIUrl":"10.1016/j.pbb.2025.174113","url":null,"abstract":"<div><div>Cocaine use disorder (CUD) remains a major public health challenge with no effective pharmacological treatments to date. Although extensive preclinical research using animal models has advanced our understanding, these findings have yet to translate into clinical success. This review highlights key independent variables that should be incorporated to improve the validity and translational relevance of animal studies. The discussion is organized around three primary domains: the agent; the host; and the environment. Most studies in this review focus on cocaine as the agent and host factors such as species and sex are emphasized as important independent variables influencing outcomes. The central theme of this review is to emphasize, from a preclinical model perspective, the critical role of environmental context, including operant conditioning parameters like schedules of reinforcement and maintaining events, as well as social housing conditions, which profoundly impact cocaine-maintained behavior and the effectiveness of interventions for cocaine self-administration.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"257 ","pages":"Article 174113"},"PeriodicalIF":2.5,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145293358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1016/j.pbb.2025.174115
Adson 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
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.
{"title":"Creatine prevents ouabain-induced manic-like behavior by modulating GSK-3β via PI3K/AKT/mTOR pathway","authors":"Adson 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":"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<sup>−3</sup> M), a Na<sup>+</sup>/K<sup>+</sup>-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<sup>+</sup>/K<sup>+</sup>-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":"2025-10-10","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}
Pub Date : 2025-10-09DOI: 10.1016/j.pbb.2025.174112
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
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.
{"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":"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":"2025-10-09","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}
Pub Date : 2025-10-09DOI: 10.1016/j.pbb.2025.174111
Annie K. Griffith, Mark T. Fillmore
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.
{"title":"Sex differences in acute tolerance to the objective and subjective effects of alcohol","authors":"Annie K. Griffith, 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}
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