Pub Date : 2025-12-12DOI: 10.1016/j.pbb.2025.174144
Alena Lemeshova , Kaya A. Patel , Alexander J. Bloom, Lindsay Golan, Haney Haidari, Aiman Limbada, Cherish Zhao, Jennifer A. Honeycutt
Background
Ketamine, a nonselective NMDA-receptor antagonist, is an emerging therapeutic for treatment-resistant depression and could also be a promising treatment for anxiety and post-traumatic stress disorders. However, preclinical studies in these areas lack methodological standardization, limiting clinical translatability. This review evaluates ketamine's anxiolytic potential in rodents by examining outcomes among different animal models, dosages, and treatment timing.
Methods & Results
A PubMed search of studies published up to July 21, 2025, identified 562 articles assessing ketamine's effects on anxiety and PTSD in rodent models. After applying inclusion and exclusion criteria, 35 studies were analyzed. Key methodological variables, model type, dosage, and timing were summarized to assess consistency and effectiveness across studies.
Conclusion
Current research on ketamine's anxiolytic potential in rodents is limited by inconsistent methods and inadequate sex inclusion. Evidence suggests that administering 10 to 30 mg/kg intraperitoneally and waiting ≥24 h before behavioral testing procedures produces anxiolytic effects, in deficit models. Future studies should include female subjects and standardized designs to enhance clinical translatability and relevance.
{"title":"A systematic review of ketamine's anxiolytic potential in rodent behavioral models of anxiety and PTSD","authors":"Alena Lemeshova , Kaya A. Patel , Alexander J. Bloom, Lindsay Golan, Haney Haidari, Aiman Limbada, Cherish Zhao, Jennifer A. Honeycutt","doi":"10.1016/j.pbb.2025.174144","DOIUrl":"10.1016/j.pbb.2025.174144","url":null,"abstract":"<div><h3>Background</h3><div>Ketamine, a nonselective NMDA-receptor antagonist, is an emerging therapeutic for treatment-resistant depression and could also be a promising treatment for anxiety and post-traumatic stress disorders. However, preclinical studies in these areas lack methodological standardization, limiting clinical translatability. This review evaluates ketamine's anxiolytic potential in rodents by examining outcomes among different animal models, dosages, and treatment timing.</div></div><div><h3>Methods & Results</h3><div>A PubMed search of studies published up to July 21, 2025, identified 562 articles assessing ketamine's effects on anxiety and PTSD in rodent models. After applying inclusion and exclusion criteria, 35 studies were analyzed. Key methodological variables, model type, dosage, and timing were summarized to assess consistency and effectiveness across studies.</div></div><div><h3>Conclusion</h3><div>Current research on ketamine's anxiolytic potential in rodents is limited by inconsistent methods and inadequate sex inclusion. Evidence suggests that administering 10 to 30 mg/kg intraperitoneally and waiting ≥24 h before behavioral testing procedures produces anxiolytic effects, in deficit models. Future studies should include female subjects and standardized designs to enhance clinical translatability and relevance.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174144"},"PeriodicalIF":2.5,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757177","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 : 2025-12-08DOI: 10.1016/j.pbb.2025.174143
Larysa Bondarenko , Tetiana Karatsuba , Alla Voronina , Maksim Munko , Valentina Kovalenko , Ganna Shayakhmetova
Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder, with neuroendocrine, metabolic, and immune alterations accompanying its behavioral symptoms. While selective serotonin reuptake inhibitors such as fluoxetine are widely used to treat PTSD, their systemic effects during critical developmental periods remain poorly understood. Using a peripubertal rat model of PTSD-like stress, we evaluated the effects of fluoxetine administered during puberty on behavior (passive avoidance), serum biochemistry, hematology, and IL-6 levels. Assessments were conducted in two phases: shortly following the end of fluoxetine treatment and in a delayed post-treatment period. PTSD-like stress enhanced aversive memory retention, an effect attenuated by fluoxetine in the short post-treatment phase but not in the delayed period. Uric acid content in serum was increased in both PTSD and PTSD+fluoxetine groups shortly post-treatment, while LDL elevation was observed only in the delayed phase. The long-term effect of fluoxetine on serum creatinine was observed. Additional hematological alterations were observed in the delayed period. Serum IL-6 levels remained persistently elevated in PTSD group across both phases, indicating sustained inflammation with no clear effect of fluoxetine. Thus, peripubertal PTSD-like stress induces behavioral and metabolic alterations that persist beyond the acute stress period. Fluoxetine partially normalized behavior but failed to prevent long-term biochemical and hematological alterations. These highlight the systemic and time-dependent consequences of peripubertal PTSD and its pharmacological treatment, underscoring the need for longitudinal monitoring of physiological outcomes alongside recovery of behavioral phenotype.
{"title":"Peripubertal PTSD-like stress in rats induces transient behavioral but lasting metabolic and inflammatory alterations: Limited fluoxetine efficacy","authors":"Larysa Bondarenko , Tetiana Karatsuba , Alla Voronina , Maksim Munko , Valentina Kovalenko , Ganna Shayakhmetova","doi":"10.1016/j.pbb.2025.174143","DOIUrl":"10.1016/j.pbb.2025.174143","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is increasingly recognized as a systemic disorder, with neuroendocrine, metabolic, and immune alterations accompanying its behavioral symptoms. While selective serotonin reuptake inhibitors such as fluoxetine are widely used to treat PTSD, their systemic effects during critical developmental periods remain poorly understood. Using a peripubertal rat model of PTSD-like stress, we evaluated the effects of fluoxetine administered during puberty on behavior (passive avoidance), serum biochemistry, hematology, and IL-6 levels. Assessments were conducted in two phases: shortly following the end of fluoxetine treatment and in a delayed post-treatment period. PTSD-like stress enhanced aversive memory retention, an effect attenuated by fluoxetine in the short post-treatment phase but not in the delayed period. Uric acid content in serum was increased in both PTSD and PTSD+fluoxetine groups shortly post-treatment, while LDL elevation was observed only in the delayed phase. The long-term effect of fluoxetine on serum creatinine was observed. Additional hematological alterations were observed in the delayed period. Serum IL-6 levels remained persistently elevated in PTSD group across both phases, indicating sustained inflammation with no clear effect of fluoxetine. Thus, peripubertal PTSD-like stress induces behavioral and metabolic alterations that persist beyond the acute stress period. Fluoxetine partially normalized behavior but failed to prevent long-term biochemical and hematological alterations. These highlight the systemic and time-dependent consequences of peripubertal PTSD and its pharmacological treatment, underscoring the need for longitudinal monitoring of physiological outcomes alongside recovery of behavioral phenotype.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174143"},"PeriodicalIF":2.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145725082","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}
Pain-depression morbidity affects millions, but there are no effective treatments available. Dezocine is a clinically used opioid analgesic with complicated pharmacological mechanisms. Given this unique pharmacological profile and the crucial involvement of noradrenergic/serotonergic systems in the pathophysiology of depression, dezocine might be able to relieve pain-depression comorbidity. This possibility has not been tested and is the focus of this study. However, this potential has not yet been empirically validated, and investigating it constitutes the primary aim of this study.
Methods
Animal models of depression (Lipopolysaccharides [LPS] and chronic unpredictable mild stress models [CUMS]) were established, and two neuropathic pain models (chronic constriction injury [CCI] and spared nerve injury [SNI]) were used to establish chronic pain-induced depressive-like behaviors and the antidepressive-like effects of dezocine were then examined. Tail suspension test (TST) and force swimming test (FST) were used as behavioral readouts of antidepressant effects. For receptor mechanisms studies, 5-HT1A receptor antagonist WAY-100635, nonselective opioid receptor antagonist naltrexone [NTX]), and three selective opioid receptor antagonists (μ: CTAP; δ: naltrindole [NAL]; k: nor-binaltorphimine [nor-BNI]) were used as pretreatment to antagonize the effects of dezocine.
Results
Dezocine (5 and 10 mg/kg, i.p.) significantly reduced immobility time, suggesting its robust antidepressive-like effects in stand-alone depression models and in neuropathic pain-induced depression models. WAY-100635, NTX, and CTAP but not NAL or nBNI blocked the antidepressive-like effects of dezocine, suggesting the involvement of 5-HT1A and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.
Conclusion
This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT1A and μ-opioid receptor.
{"title":"Dual activation of 5-HT1A and μ-opioid receptors mediates dezocine's antidepressant effects in mice with comorbid pain and depression","authors":"Qian-Qian Wei , Kun-Hong Zhong , Xiao-Ke Zhang , Liangxue Zhou , Qing Zhu , Junxu Li","doi":"10.1016/j.pbb.2025.174136","DOIUrl":"10.1016/j.pbb.2025.174136","url":null,"abstract":"<div><h3>Background</h3><div>Pain-depression morbidity affects millions, but there are no effective treatments available. Dezocine is a clinically used opioid analgesic with complicated pharmacological mechanisms. Given this unique pharmacological profile and the crucial involvement of noradrenergic/serotonergic systems in the pathophysiology of depression, dezocine might be able to relieve pain-depression comorbidity. This possibility has not been tested and is the focus of this study. However, this potential has not yet been empirically validated, and investigating it constitutes the primary aim of this study.</div></div><div><h3>Methods</h3><div>Animal models of depression (Lipopolysaccharides [LPS] and chronic unpredictable mild stress models [CUMS]) were established, and two neuropathic pain models (chronic constriction injury [CCI] and spared nerve injury [SNI]) were used to establish chronic pain-induced depressive-like behaviors and the antidepressive-like effects of dezocine were then examined. Tail suspension test (TST) and force swimming test (FST) were used as behavioral readouts of antidepressant effects. For receptor mechanisms studies, 5-HT<sub>1A</sub> receptor antagonist WAY-100635, nonselective opioid receptor antagonist naltrexone [NTX]), and three selective opioid receptor antagonists (μ: CTAP; δ: naltrindole [NAL]; k: nor-binaltorphimine [nor-BNI]) were used as pretreatment to antagonize the effects of dezocine.</div></div><div><h3>Results</h3><div>Dezocine (5 and 10 mg/kg, i.p.) significantly reduced immobility time, suggesting its robust antidepressive-like effects in stand-alone depression models and in neuropathic pain-induced depression models. WAY-100635, NTX, and CTAP but not NAL or nBNI blocked the antidepressive-like effects of dezocine, suggesting the involvement of 5-HT<sub>1A</sub> and μ-opioid receptors in mediating the antidepressive-like effects of dezocine.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that dezocine alleviates pain-depression comorbidity by activating both 5-HT<sub>1A</sub> and μ-opioid receptor.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174136"},"PeriodicalIF":2.5,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715290","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 : 2025-12-05DOI: 10.1016/j.pbb.2025.174135
Daniel A. Palacios-Lagunas , Juan C. Hernández-Mondragón , Kjell Fuxe , Dasiel O. Borroto-Escuela , Minerva Crespo-Ramírez , Francisco Pérez-Eugenio , Miguel Pérez de la Mora
The promotion of prosocial behavior is a remarkable MDMA property. Such an effect is rather uncommon among other psychoactive substances and has been proposed to be of relevance for the potential therapeutic utility of MDMA. We aim to expand our knowledge of the prosocial effects of MDMA, considering sex and housing conditions as extra variables. To this end, housed individually or collectively, male and female Wistar rats were tested using the Social Preference paradigm.
Contrary to expectations, MDMA treatment reduced the prosocial behavior in male rats, irrespective of the housing conditions. Similar effects are observed in female rats, but only in those individually housed. Intriguingly, no MDMA social effects were observed on those female rats, which are collectively housed. Also interesting was the apparent existence of two subgroups of rats that responded differentially to the MDMA administration, suggesting that individual variations among rats may influence the degree of their response to the MDMA treatment. More work is needed to understand how differences across individuals are relevant to the behavioral effects of MDMA.
{"title":"The 3,4-methylenedioxymethamphetamine (MDMA) reduces prosocial behavior in the social preference test in male and female rats","authors":"Daniel A. Palacios-Lagunas , Juan C. Hernández-Mondragón , Kjell Fuxe , Dasiel O. Borroto-Escuela , Minerva Crespo-Ramírez , Francisco Pérez-Eugenio , Miguel Pérez de la Mora","doi":"10.1016/j.pbb.2025.174135","DOIUrl":"10.1016/j.pbb.2025.174135","url":null,"abstract":"<div><div>The promotion of prosocial behavior is a remarkable MDMA property. Such an effect is rather uncommon among other psychoactive substances and has been proposed to be of relevance for the potential therapeutic utility of MDMA. We aim to expand our knowledge of the prosocial effects of MDMA, considering sex and housing conditions as extra variables. To this end, housed individually or collectively, male and female Wistar rats were tested using the Social Preference paradigm.</div><div>Contrary to expectations, MDMA treatment reduced the prosocial behavior in male rats, irrespective of the housing conditions. Similar effects are observed in female rats, but only in those individually housed. Intriguingly, no MDMA social effects were observed on those female rats, which are collectively housed. Also interesting was the apparent existence of two subgroups of rats that responded differentially to the MDMA administration, suggesting that individual variations among rats may influence the degree of their response to the MDMA treatment. More work is needed to understand how differences across individuals are relevant to the behavioral effects of MDMA.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"259 ","pages":"Article 174135"},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701244","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 : 2025-11-29DOI: 10.1016/j.pbb.2025.174134
Yonca Cam , Carlos A. Sardina , Sanya K. Suri , Elizabeth C. Pickering , Felicia M. Padilla , Matthew J. Will
Melanin-concentrating hormone (MCH) system within the nucleus accumbens (Acb) has been shown to regulate feeding behavior; however, the interaction between MCH and opioid-driven hedonic eating remains unclear. This study investigated the effects of intra-Acb administration of the MCHR1 antagonist SNAP-94847 on opioid-driven sucrose pellet intake in male and female rats. Subjects received MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/0.5 μl/side) immediately prior to intra-Acb administration of the μ-opioid receptor agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0 μg and 0.025 μg/0.5 μl/side) before completing free-feeding tests. Results showed that DAMGO significantly increased sucrose pellet intake in both sexes, while SNAP-94847 alone had no effect, nor did it block the DAMGO-induced increase in either males or females. This finding suggests that MCHR1 within the Acb does not play a significant role in low-effort palatability-driven motivation for food consumption, contrasting with its role in effort-based motivation tasks.
{"title":"Intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonism on opioid-driven sucrose consumption in male and female rats","authors":"Yonca Cam , Carlos A. Sardina , Sanya K. Suri , Elizabeth C. Pickering , Felicia M. Padilla , Matthew J. Will","doi":"10.1016/j.pbb.2025.174134","DOIUrl":"10.1016/j.pbb.2025.174134","url":null,"abstract":"<div><div>Melanin-concentrating hormone (MCH) system within the nucleus accumbens (Acb) has been shown to regulate feeding behavior; however, the interaction between MCH and opioid-driven hedonic eating remains unclear. This study investigated the effects of intra-Acb administration of the MCHR1 antagonist SNAP-94847 on opioid-driven sucrose pellet intake in male and female rats. Subjects received MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/0.5 μl/side) immediately prior to intra-Acb administration of the μ-opioid receptor agonist, D-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO; 0 μg and 0.025 μg/0.5 μl/side) before completing free-feeding tests. Results showed that DAMGO significantly increased sucrose pellet intake in both sexes, while SNAP-94847 alone had no effect, nor did it block the DAMGO-induced increase in either males or females. This finding suggests that MCHR1 within the Acb does not play a significant role in low-effort palatability-driven motivation for food consumption, contrasting with its role in effort-based motivation tasks.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174134"},"PeriodicalIF":2.5,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145621255","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 : 2025-11-20DOI: 10.1016/j.pbb.2025.174133
Joo Hye Sim , Hye Jin Choi , Ohhyeon Kwon , Taeyeon Kim , Doheon Lee , Jeong June Choi
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.
{"title":"1,4-Naphthoquinone improves depressive-like behaviors by modulating neuronal factors and neuroinflammatory mediators","authors":"Joo Hye Sim , Hye Jin Choi , Ohhyeon Kwon , Taeyeon Kim , Doheon Lee , 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":"2025-11-20","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}
Pub Date : 2025-11-17DOI: 10.1016/j.pbb.2025.174131
Daisuke Ibi , Keisuke Ishida , Takaaki Kojima , Shuri Yoshida , Anna Suzuki , Serina Suzuki , Mai Yasui , Kotarou Shibuya , Moe Nakanishi , Tomoe Yamagami , Justin M. Saunders , Mario de la Fuente Revenga , Javier Gonzalez-Maeso , Masayuki Hiramatsu
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 (Egr1), 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 Hdac2 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 Hdac2 deletion. Hdac2 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 Hdac2 deletion. Additionally, continuous microinjection of recombinant BDNF protein into the ventricle accelerated kindling in mice with Hdac2 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.
{"title":"EGR1-mediated repression of HDAC2 regulates BDNF-dependent kindling development in a mouse model of pentylenetetrazol-induced epilepsy","authors":"Daisuke Ibi , Keisuke Ishida , Takaaki Kojima , Shuri Yoshida , Anna Suzuki , Serina Suzuki , Mai Yasui , Kotarou Shibuya , Moe Nakanishi , Tomoe Yamagami , Justin M. Saunders , Mario de la Fuente Revenga , Javier Gonzalez-Maeso , 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":"2025-11-17","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}
Pub Date : 2025-11-14DOI: 10.1016/j.pbb.2025.174130
Alexa R. Soares , Caroline Fai , Yann S. Mineur , Marina R. Picciotto
Norepinephrine (NE) signaling is disrupted in stress disorders, with insufficient NE signaling implicated in major depressive disorder and hyperactive NE signaling associated with post-traumatic stress disorder, suggesting that adequate mood regulation requires optimal NE levels. The basolateral amygdala (BLA) is a hub for stress processing and receives dense noradrenergic innervation from the locus coeruleus (LC), the primary noradrenergic nucleus in the brain. The relationship between LC activity and cognitive/behavioral function during fear conditioning has been described as an inverted U, in which moderate LC activity, and subsequent NE release, is required for adaptive coping to threats, while hyperactive LC-NE signaling drives maladaptive behavioral responses. We used fiber photometry to measure NE signaling in the mouse BLA during acute behavioral responses to escapable and inescapable stressors, and then used an optogenetic approach to stimulate the noradrenergic terminals in the BLA at different frequencies to evaluate effects on coping behavior and cFos expression in the LC-BLA circuit. We found that low-frequency stimulation of the circuit inhibited both passive coping and BLA neuronal activity, while high-frequency stimulation had the opposite effect; the behavioral effects were not mediated by sex, but the cFos effects were specific to males. This study represents an expansion of the inverted U framework to encompass LC-BLA signaling driving acute behavioral responses to stress.
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Pub Date : 2025-11-14DOI: 10.1016/j.pbb.2025.174132
Michael A. Taffe , Tyra R. Coons , Tess A. Doran , Yanabel Grant , Sophia A. Vandewater
Rationale
The nicotine analog 6-methyl nicotine (6-MN) has recently appeared in non-tobacco nicotine delivery products, including oral pouches and e-cigarette liquids, in an apparent ploy to evade regulation of nicotine by the United States Food and Drug Administration or other public health agencies. Unfortunately, only minimal scientific information on the effects of 6-MN is available.
Objective
To determine the extent to which 6-MN produces nicotine-like effects on body temperature, wheel activity and nociception in laboratory rodents.
Methods
Middle-aged (starting at Post Natal Day 425) female Wistar rats were evaluated for rectal temperature, voluntary wheel activity, and nociceptive responses (warm water tail-withdrawal) to subcutaneous injection of nicotine (0.0, 0.8 mg/kg) or 6-methyl nicotine (6-MN; 0.0, 0.4, 0.8 mg/kg). Temperature and nociceptive responses to vapor inhalation of 6-MN [0–30 mg/mL in the propylene glycol (PG) vehicle] were assessed. Finally, the self-administration of 6-MN vapor was compared with nicotine vapor self-administration.
Results
6-MN decreased rectal temperature, suppressed wheel activity and induced modest nociceptive effects. The magnitude of the effect of 0.8 mg/kg 6-MN and 0.8 mg/kg nicotine were similar across all three assays. Vapor self-administration of 6-MN and nicotine was likewise comparable at a 10 mg/mL concentration.
Conclusion
6-MN administered by injection or by vapor inhalation produces behavioral and physiological effects that are very similar to those produced by nicotine in rats. It is therefore likely that detrimental health effects of 6-MN will be quite similar to those established for nicotine.
{"title":"6-Methyl nicotine and nicotine have similar thermoregulatory and reinforcing effects in middle aged female rats with a history of nicotine vapor self-administration","authors":"Michael A. Taffe , Tyra R. Coons , Tess A. Doran , Yanabel Grant , Sophia A. Vandewater","doi":"10.1016/j.pbb.2025.174132","DOIUrl":"10.1016/j.pbb.2025.174132","url":null,"abstract":"<div><h3>Rationale</h3><div>The nicotine analog 6-methyl nicotine (6-MN) has recently appeared in non-tobacco nicotine delivery products, including oral pouches and e-cigarette liquids, in an apparent ploy to evade regulation of nicotine by the United States Food and Drug Administration or other public health agencies. Unfortunately, only minimal scientific information on the effects of 6-MN is available.</div></div><div><h3>Objective</h3><div>To determine the extent to which 6-MN produces nicotine-like effects on body temperature, wheel activity and nociception in laboratory rodents.</div></div><div><h3>Methods</h3><div>Middle-aged (starting at Post Natal Day 425) female Wistar rats were evaluated for rectal temperature, voluntary wheel activity, and nociceptive responses (warm water tail-withdrawal) to subcutaneous injection of nicotine (0.0, 0.8 mg/kg) or 6-methyl nicotine (6-MN; 0.0, 0.4, 0.8 mg/kg). Temperature and nociceptive responses to vapor inhalation of 6-MN [0–30 mg/mL in the propylene glycol (PG) vehicle] were assessed. Finally, the self-administration of 6-MN vapor was compared with nicotine vapor self-administration.</div></div><div><h3>Results</h3><div>6-MN decreased rectal temperature, suppressed wheel activity and induced modest nociceptive effects. The magnitude of the effect of 0.8 mg/kg 6-MN and 0.8 mg/kg nicotine were similar across all three assays. Vapor self-administration of 6-MN and nicotine was likewise comparable at a 10 mg/mL concentration.</div></div><div><h3>Conclusion</h3><div>6-MN administered by injection or by vapor inhalation produces behavioral and physiological effects that are very similar to those produced by nicotine in rats. It is therefore likely that detrimental health effects of 6-MN will be quite similar to those established for nicotine.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"258 ","pages":"Article 174132"},"PeriodicalIF":2.5,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145533854","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 : 2025-11-11DOI: 10.1016/j.pbb.2025.174129
A.S. Rauhut , K. Mehta , N. Fedorczak , J. Henderson , H. Holdaway , G.B. Rauhut
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.
{"title":"Post-conditioning catecholaminergic antagonism fails to alter methamphetamine sensitization in mice","authors":"A.S. Rauhut , K. Mehta , N. Fedorczak , J. Henderson , H. Holdaway , 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":"2025-11-11","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}
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