Neuropharmacology最新文献

{"title":"Intrinsic activation of the coagulation pathway induces mouse sciatic nerve hypoexcitability","authors":"Shani Berkowitz ,&nbsp;Valery Golderman ,&nbsp;Zehavit Goldberg ,&nbsp;Joab Chapman ,&nbsp;Amir Dori ,&nbsp;Nicola Maggio ,&nbsp;Jérôme Joël Devaux ,&nbsp;Efrat Shavit-Stein","doi":"10.1016/j.neuropharm.2025.110569","DOIUrl":"10.1016/j.neuropharm.2025.110569","url":null,"abstract":"<div><h3>Background</h3><div>Thrombin and its protease-activated receptor 1 (PAR1) modulate neuronal function in experimental settings, but the effects of activating intrinsic neuronal coagulation factors remain unclear. We investigated how activation of this pathway influences peripheral nerve function in an isolated mouse sciatic nerve model.</div></div><div><h3>Methods</h3><div>We used an <em>ex vivo</em> mouse sciatic nerve model to evaluate the effects of coagulation activation on neural excitability. Isolated nerves from male C57BL/6J mice were treated with Russell's viper venom factor X (FX) activator (RVV-X, 0.3 U/ml), FX inhibitor (apixaban, 1 μM), thrombin (200 U/ml), or a PAR1 antagonist (SCH 79797, 1 μM). Electrophysiological recordings assessed evoked neural responses. Thrombin and FX activity were quantified in tissue and artificial cerebrospinal fluid (aCSF). mRNA and immunofluorescence analyses localized coagulation-related components.</div></div><div><h3>Results</h3><div>RVV-X and thrombin treatments significantly attenuated neural responses to repeated stimulation (p &lt; 0.0001), while apixaban and the PAR1 antagonist prevented these effects (p &gt; 0.9999). RVV-X markedly increased thrombin activity in aCSF (p &lt; 0.0001). mRNA and immunofluorescence analyses confirmed that coagulation-related components were primarily expressed in the paranodal region of the sciatic nerve.</div></div><div><h3>Conclusions</h3><div>The FX-thrombin pathway is intrinsically present and functionally active in sciatic nerves of mice. Activation of this pathway reduces neuronal excitability via PAR1, suggesting a finely tuned feedback mechanism between coagulation factors and neural function. These findings highlight the potential role of coagulation-mediated mechanisms in peripheral nerve pathologies, which may serve as biomarkers and therapeutic targets for neurological diseases.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110569"},"PeriodicalIF":4.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histaminergic transmission potentiates post-traumatic stress-induced expression of anxiety in mice","authors":"Vaibhav Maturkar,&nbsp;Richa Patel,&nbsp;Chhatrapal Patel,&nbsp;Venu Anand Das Vaishnav,&nbsp;Nishant Sudhir Jain","doi":"10.1016/j.neuropharm.2025.110564","DOIUrl":"10.1016/j.neuropharm.2025.110564","url":null,"abstract":"<div><div>Post-traumatic stress is associated with an increased expression of anxiety traits and is reported to be accompanied by altered brain histamine content. However, the contribution of the central histaminergic system in the stress induced anxiety, still remains unclear. Therefore, the present study explored the plausible role of central histaminergic transmission in stress-induced anxiety measures in mice using LDB test and in the expression of CORT, CREB, or BDNF levels in the whole brain, PFC, amygdala, and hippocampus of mice. The mice were exposed to the SPS protocol and subsequently left undisturbed for 7 days. On the 8th day, non-SPS/SPS exposed mice were treated i.c.v with histaminergic agents such as histamine, or histamine precursor, l-histidine, H₁ agonist, FMPH, H₂ agonist, amthamine, H₁ antagonist, cetirizine or H₂ antagonist, ranitidine or H₃ inverse agonist, thioperamide and thereafter evaluated for changes in expression of anxiety followed by estimation of CORT, CREB and BDNF levels in brain. Results revealed that SPS-exposed mice elicit heightened anxiety-like behavior accompanied by increased levels of blood or brain histamine and CORT with reduced BDNF/CREB expression in the all-brain tissues. Administration of histaminergic enhancing agents to SPS-exposed mice potentiated the higher expression of anxiety, also further enhanced CORT, and diminished the BDNF/CREB expression in all brain regions. Conversely, central injection of the H₁ receptor antagonist, cetirizine (0.1 μg/mouse) or H₂ receptor antagonist, ranitidine (10 μg/mouse, i.c.v) to SPS mice completely alleviated all the stressed induced changes while H₃ receptor inverse agonist, thioperamide (2, 10 μg/mouse) failed to affect CORT but restored basal anxiety, CREB and BDNF expression. Thus, the blockade of central histamine H₁/H₂/H₃ receptors might mitigate SPS-induced anxiety-like manifestations by extenuating the SPS-induced CORT, CREB, and BDNF expression.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110564"},"PeriodicalIF":4.6,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent nutritional influences on the brain: implications for eating behaviors","authors":"Mary Lazzaro ,&nbsp;Austin M. Mills ,&nbsp;Emily E. Noble","doi":"10.1016/j.neuropharm.2025.110570","DOIUrl":"10.1016/j.neuropharm.2025.110570","url":null,"abstract":"<div><div>Adolescence represents a life stage in which vast physiological and neuroendocrine changes contribute to rapid growth and development. Throughout this transition from childhood to adulthood, the adolescent brain is in a critical developmental period. This is especially true for the prefrontal cortex and hippocampus, essential areas for executive functioning. The formation of lasting synaptic connections and dynamic plasticity within the adolescent brain make it especially vulnerable to environmental insults, such as a poor-quality diet. Herein, we review research pertaining to the period of adolescence with respect to food intake control as well as the impact of the modern food environment on the development of the prefrontal cortex and hippocampus and discuss implications for ingestive behaviors throughout rest of life.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110570"},"PeriodicalIF":4.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of the dorsomedial striatum impairs reversal learning in response to probabilistic uncertainty and disrupts corticostriatal function in mice","authors":"Kyna-Anne Conn ,&nbsp;Joyosmita Das ,&nbsp;Suzy Alexander ,&nbsp;Thomas HJ. Burne ,&nbsp;James P. Kesby","doi":"10.1016/j.neuropharm.2025.110568","DOIUrl":"10.1016/j.neuropharm.2025.110568","url":null,"abstract":"<div><div>People with schizophrenia often show impairments in cognitive flexibility, which is a key aspect of executive function, and this contributes to poor functional outcomes. Neuroimaging studies in schizophrenia have implicated dysfunction within the dorsomedial striatum (DMS), which is a subcortical brain region integral to reversal learning, i.e., a form of cognitive flexibility involving adapting behaviour in response to changing reward contingencies. Given its integral role in these processes, understanding the biological and cognitive consequences related to DMS dysfunction may inform therapeutic strategies to mitigate cognitive inflexibility. This study employed a serial reversal learning paradigm to examine decision-making under probabilistic uncertainty and investigated the effects of DREAADs-based chemogenetic inhibition of the DMS on performance and the subsequent activity of corticostriatal circuitry in male C57BL/6J mice. Inhibition of DMS activity impaired reversal learning under probabilistic uncertainty, specifically disrupting reward-based decision-making strategies such as by reducing win-stay behaviour. Furthermore, DMS inactivation led to diminished corticostriatal network co-activation during reversal learning, with pronounced reductions in the efficiency of anterior cingulate, orbitofrontal, and insular cortices—cortical regions crucial for flexible learning. These results suggest that inhibiting DMS function disrupts behavioural adaptation as well as corticostriatal co-activation, a mechanism that potentially contributes to the cognitive inflexibility observed in schizophrenia. By elucidating the neural substrates of reversal learning deficits, this study provides insights into the mechanisms by which DMS inhibition affects cognitive flexibility and highlights potential targets for therapeutic intervention in schizophrenia-relevant cognitive impairments.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110568"},"PeriodicalIF":4.6,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological and electrophysiological characterization of the novel Kv7 channel inhibitor racecadotril in Parkinson's disease","authors":"Bo Yang ,&nbsp;Hui Liu ,&nbsp;Shifan Zhang ,&nbsp;Biao Liu ,&nbsp;Qiaoqiao Sun ,&nbsp;Wen Li ,&nbsp;Rong Zheng ,&nbsp;Qingzhuo Cui ,&nbsp;Yulin Gu ,&nbsp;Xiaoke Li ,&nbsp;Jie Zhang ,&nbsp;Yidong Liu ,&nbsp;Fan Zhang","doi":"10.1016/j.neuropharm.2025.110565","DOIUrl":"10.1016/j.neuropharm.2025.110565","url":null,"abstract":"<div><div>Inhibition of KCNQ-encoded voltage-gated potassium Kv7/M channel function represents an attractive therapeutic strategy for Parkinson's disease (PD). Racecadotril (acetorphan), an inhibitor of the enzyme neutral endopeptidase, has been clinically used to treat acute diarrhea. In this study, we investigated the effects of racecadotril through recording the Kv7.1-Kv7.5 channel currents expressed in CHO cell lines. Our results demonstrate that racecadotril inhibited Kv7.2/Kv7.3 currents in a concentration-dependent manner, with an IC₅₀ value of 7.1 ± 0.83 μM. Racecadotril significantly right-shifted the voltage-dependent activation curve of the Kv7.2/Kv7.3 channels. Additionally, it potently inhibited Kv7.1, Kv7.2, Kv7.4, and Kv7.5 channels, while exerting weak inhibitory effects on the Kv7.3 channel. Notably, we found that thiorphan, the <em>in vivo</em> metabolite of racecadotril, also significantly inhibits Kv7.2, Kv7.4, and Kv7.5 channel currents; however, it does not inhibit the Kv7.2 (W236L), Kv7.4 (W242A) or Kv7.5 (W270A) mutants. Moreover, intraperitoneal administration of racecadotril in 8-week-old male C57BL/6 mice inhibited MPTP-induced motor dysfunction in this PD model, an effect that was blocked by the Kv7 channel opener retigabine (RTG). Taken together, our findings indicate that racecadotril is a potent inhibitor of Kv7.1, Kv7.2, Kv7.4 and Kv7.5 channels, which effectively ameliorates symptoms of PD in rodents.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110565"},"PeriodicalIF":4.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting P2X7 mitigates neurobehavioural alterations in a mouse model of post-acute sequelae of SARS-CoV-2 infection","authors":"Dorottya Szabó ,&nbsp;Pál Tod ,&nbsp;Fruzsina Maácz ,&nbsp;Flóra Gölöncsér ,&nbsp;Bernadett Iring-Varga ,&nbsp;Bibiána Török ,&nbsp;Gyula Zsidei ,&nbsp;Bernadett Pályi ,&nbsp;Zoltán Kis ,&nbsp;Beáta Sperlágh","doi":"10.1016/j.neuropharm.2025.110566","DOIUrl":"10.1016/j.neuropharm.2025.110566","url":null,"abstract":"<div><div>The COVID-19 pandemic has imposed a significant global health burden, leading to various long-term consequences, including persistent neuropsychiatric symptoms in a substantial proportion of infected individuals. This study investigates the role of the purinergic receptor P2X7 in mediating behaviour changes in a mouse model of post-acute sequelae of SARS-CoV-2 infection (PASC). We show that infection with a mouse-adapted SARS-CoV-2 strain induces anxiety- and depression-like behaviours in male mice, associated with elevated P2X7 receptor expression in the prefrontal cortex and hippocampus, as well as increased IFN-γ levels in the striatum. To assess the therapeutic potential of P2X7 antagonism, we administered the selective P2X7 antagonist JNJ 47965567 <em>in vivo</em>. Pretreatment with JNJ 47965567 mitigated the behavioural changes and reduced IFN-γ levels, suggesting a potential therapeutic role for P2X7 antagonists in the management of post-COVID neuropsychiatric symptoms. Our findings support the involvement of neuroinflammation in the symptoms of PASC and highlight the P2X7 pathway as a potential innovative therapeutic target for alleviating anxiety and depression in affected individuals and in other sequelae of post-viral neuropsychiatric conditions.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110566"},"PeriodicalIF":4.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144314399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological and pharmacokinetic study of Isobutyryfentanyl in female and male CD1 Mice","authors":"Sabrine Bilel ,&nbsp;Camilla Montesano ,&nbsp;Micaela Tirri ,&nbsp;Giorgia Corli ,&nbsp;Marta Bassi ,&nbsp;Fabiana Di Rosa ,&nbsp;Adolfo Gregori ,&nbsp;Manuel Sergi ,&nbsp;Matteo Marti","doi":"10.1016/j.neuropharm.2025.110563","DOIUrl":"10.1016/j.neuropharm.2025.110563","url":null,"abstract":"<div><div>Despite the decline of fentanyl and its analogs seizure in Europe, these synthetic opioids continue to be detected in many cases of death. Moreover, there is a scarce literature regarding the pharmacology and the pharmacokinetic of these drugs. This study is aimed to i) assess the in vivo pharmacological effects of the fentanyl analog Isobutyrylfentanyl (IBF) in male and female mice administered an intraperitoneal dose of 5 mg/kg, ii) determine the pharmacokinetic profiles in plasma, urine and tissues of both sexes, and iii) correlate the behavioral and physiological effects with IBF plasma levels in males and females. Sex differences were observed in the behavioral and pharmacokinetic effects of IBF. IBF showed a persistent motor and analgesic effects after 24h of measurements. Females consistently exhibited more pronounced and longer-lasting responses, particularly in motor and sensorimotor tests, and showed slower drug elimination. In contrast, males demonstrated stronger responses in vibrissae reflex tests and had a faster clearance of IBF. These results underscore the importance of accounting for sex as a biological variable in pharmacological research, with potential implications for clinical and forensic applications.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110563"},"PeriodicalIF":4.6,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of orally self-administered furanyl fentanyl and acryl fentanyl in mice: antinociception, dependence and withdrawal, and defense of consumption","authors":"Brenda M. Gannon ,&nbsp;Mary E. Shepard ,&nbsp;Justin M. Pressley ,&nbsp;Hannah E. Shaw ,&nbsp;Kayla J. Wolf ,&nbsp;Marina Avram ,&nbsp;Jeffery H. Moran ,&nbsp;William E. Fantegrossi","doi":"10.1016/j.neuropharm.2025.110562","DOIUrl":"10.1016/j.neuropharm.2025.110562","url":null,"abstract":"<div><div>Oral use of illicit fentanyl formulations is common, and these preparations may be contaminated with fentanyl analogs (FAs) with unknown pharmacological and toxicological properties. Route of administration impacts pharmacological effects, and pharmacokinetic or pharmacodynamic properties of oral fentanyl and FAs could influence aspects of opioid use disorder that are not necessarily present in animal models involving other routes of administration. We established oral consumption of water, or solutions of the FAs furanyl fentanyl and acryl fentanyl in C57 B l/6N mice. Consumption of pharmacologically-relevant concentrations of the FAs was reliably engendered, verified by induction of opioid-mediated antinociceptive effects in a warm-water tail withdrawal procedure, hypothermic effects, and observation of antagonist-precipitated withdrawal. When maintenance solutions were adulterated with the bitter tastant quinine, water control mice decreased their consumption, but mice consuming FA solutions defended their consumption, even at quinine concentrations that suppressed water drinking. Brief access to supplemental water, injection of the μ-opioid antagonist naltrexone, or administration of the μ-opioid agonist morphine all attenuated the defense of FA consumption. In all cases, the abuse-related effects of acryl fentanyl were greater than those of furanyl fentanyl. Consumption of acryl fentanyl also abolished weight gain across the study, and disrupted nest-building. The results of these experiments suggest that mice drinking furanyl fentanyl or acryl fentanyl experience opioid-mediated effects including antinociception, dependence and withdrawal, and abuse-related subjective effects, and provide proof of concept for use of this model to assess pharmacological and non-pharmacological manipulations which may attenuate the reinforcing effects of oral fentanyl and FAs.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110562"},"PeriodicalIF":4.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent COX-2 upregulation in L-DOPA-induced dyskinesia is unaffected by inhibition with celecoxib","authors":"Maurício dos Santos Pereira ,&nbsp;Elaine Del Bel","doi":"10.1016/j.neuropharm.2025.110560","DOIUrl":"10.1016/j.neuropharm.2025.110560","url":null,"abstract":"<div><div>Neuroinflammation is a major contributor to L-DOPA-induced dyskinesia (LID), a common complication in Parkinson's disease (PD) therapy. Cyclooxygenase-2 (COX-2), a key proinflammatory enzyme, is elevated in the lesioned striatum of dyskinetic models, though its role as a causal factor or consequence remains unclear. This study addresses two aims: 1 - to explore COX-2 expression patterns in hemiparkinsonian dyskinetic mice with partial nigrostriatal lesion, correlating these patterns with the severity of abnormal involuntary movements (AIMs) and FosB/ΔFosB expression; 2- to evaluate the efficacy of COX-2 inhibitors in alleviating the established LID or preventing its development. In the first part, C57Bl/6 male mice had their AIMs intensity scored and were euthanized at 1, 7, 14, or 21 days after L-DOPA administration for molecular analysis. In the second part, mice with previously established LID were treated with either vehicle, the selective COX-2 inhibitor Celecoxib, or a non-selective COX inhibitor, Indomethacin for 5 days. An additional group received Celecoxib alongside L-DOPA for 21 days during LID development. COX-2 expression was associated with LID development after 14 days of L-DOPA treatment, correlating with AIMs severity and FosB/ΔFosB expression. COX-2 was found in striatal regions lacking tyrosine hydroxylase fibers and co-localized with neuronal markers. Although COX-2 inhibition did not reduce AIMs or COX-2 and FosB/ΔFosB expression, it significantly lowered PGE₂ levels, a downstream product of the COX-2 pathway. These results suggest that COX-2 upregulation may contribute to LID persistence through mechanisms beyond classical PGE₂-mediated neuroinflammation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110560"},"PeriodicalIF":4.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144291256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute carbamoylated erythropoietin reduces social stress-induced anxiety and depression-related behaviors","authors":"Jazmine D.W. Yaeger ,&nbsp;Megan M. John ,&nbsp;Leighton J. Ledesma ,&nbsp;Kevin T. Krupp ,&nbsp;Clarissa D. Booth ,&nbsp;Nathan T. Jones ,&nbsp;Aisel Valiño ,&nbsp;Nathan Popp ,&nbsp;Monica Sathyanesan ,&nbsp;Samuel S. Newton ,&nbsp;Cliff H. Summers","doi":"10.1016/j.neuropharm.2025.110558","DOIUrl":"10.1016/j.neuropharm.2025.110558","url":null,"abstract":"<div><div>The hormone and trophic factor Erythropoietin (EPo) promotes red blood cell production and has neurotrophic effects, modulating behavior and promoting neural plasticity, like neurogenesis. Modifying EPo by attaching a carbamoyl group (cEPo) results in similar neuronal effects without erythropoietic actions. We hypothesize that neuroplastic and learning effects of cEPo may be dependent on its action in dorsal dentate gyrus of the hippocampus, where neurogenesis occurs. The Stress Alternatives Model (SAM) is a 4-day social stress and decision-making paradigm with a large novel aggressor that provides opportunities to avoid interaction via escape routes. Early, male test mice display stable Escape (avoiding aggression) or Stay (acquiescence to aggressor) behavioral phenotypes. In these studies, mice were given a single intracerebroventricular (icv; 100 ng), or single intra-dentate gyrus (iDG; 10 ng) injection of cEPo or vehicle. By Day 4, 30% of icv cEPo treated mice and 37.5% of iDG cEPo treated mice reversed their phenotype (Stay to Escape). Mice receiving vehicle injections did not change. Normalization of social preference, and reduction in fear freezing behavior, after cEPo treatment, coincide with transcriptional changes of orexin receptors (<em>Hcrtr₁</em> &amp; <em>Hcrtr₂</em>) in the hippocampus, including phenotype- and treatment-dependent alterations in learning-associated molecular signaling molecules. Hippocampal <em>Hcrtr₁</em> moderately colocalize with EPo receptors (<em>Epor</em>) in the dentate gyrus, while <em>Hcrtr₂</em> is expressed with <em>Epor</em> in CA₁. Anxiolytic actions of cEPo during social interaction indicate mechanisms that influence learning in stressful situations, suggesting that cEPo may be a novel agent for treatment of comorbid conditions related to anxiety, depression, and PTSD.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"278 ","pages":"Article 110558"},"PeriodicalIF":4.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}