Psychopharmacology最新文献

{"title":"Mu or delta opioid receptor antagonists increase the expression of social conditioned place preference in early adolescent mice.","authors":"Zofia Harda, Marta Klimczak, Klaudia Misiołek, Magdalena Chrószcz, Aleksandra Rzeszut, Łukasz Szumiec, Maria Kaczmarczyk-Jarosz, Rafał Ryguła, Barbara Ziółkowska, Jan Rodriguez Parkitna","doi":"10.1007/s00213-025-06902-y","DOIUrl":"https://doi.org/10.1007/s00213-025-06902-y","url":null,"abstract":"<p><strong>Rationale: </strong>Social behaviors undergo dramatic changes during adolescence, enabling the development of adult social abilities. These changes are intricately linked to the development of the brain reward system and the activity of endogenous opioid signaling. However, the involvement of the opioid system in the development of social behaviors still raises more questions than answers.</p><p><strong>Objectives: </strong>Here, we investigated the role of the endogenous opioid system in the rewarding effects of social contact in early and late adolescent male mice.</p><p><strong>Methods: </strong>Social reward was assessed using the social conditioned place preference task in early adolescent (~ 34 days old) and late adolescent (~ 41 days old) male mice that received a single dose of the selective opioid receptor antagonists cyprodime (1 mg/kg, i.p.), naltrindole (1 mg/kg, i.p.) or norbinaltorphimine (10 mg/kg, i.p.) before the preference posttest.</p><p><strong>Results: </strong>The administration of cyprodime or naltrindole before the posttest significantly increased the preference for the social-conditioned context in early but not late adolescent mice. In contrast, pretreatment with norbinaltorphimine had no effect on context preference.</p><p><strong>Conclusions: </strong>Our findings support a modified version of the state-dependent mu-opioid receptor model of social behavior, where the effects of opioid ligands are not reversed during development but rather weaken or disappear with age. Furthermore, the results indicate that interactions with siblings in early adolescent mice are motivated by negative reinforcement, whereas those in late adolescence are motivated by positive reinforcement.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of legal-market cannabis and alcohol on verbal learning and memory.","authors":"Joshua L Gowin, Vanessa Stallsmith, Katelyn Weldon, Gregory Dooley, Hollis C Karoly","doi":"10.1007/s00213-025-06882-z","DOIUrl":"https://doi.org/10.1007/s00213-025-06882-z","url":null,"abstract":"<p><strong>Rationale: </strong>Widespread legalization of cannabis in the US in recent years has coincided with increasing use of alcohol and cannabis at the same time. Cannabis is thought to confer synergistic effects on alcohol intoxication, and the potential for increased cognitive impairment is a concern. Most prior co-administration studies have relied on low-THC cannabis, limiting generalizability to real-world consumption of higher-THC, legal-market cannabis.</p><p><strong>Objectives: </strong>We tested whether legal-market cannabis confers verbal learning and memory impairment beyond the effects of an acute dose of alcohol in a sample of heavy-drinking adults who regularly use cannabis.</p><p><strong>Methods: </strong>Participants (N = 60, 40% female) completed two laboratory sessions: an Alcohol Only session and a Cannabis + Alcohol session. At each session, participants completed the Rey Auditory Verbal Learning Test before and after alcohol/cannabis use. Linear mixed-effects models evaluated effects of substance use condition and sex on number of words recalled immediately and after a short and long delay.</p><p><strong>Results: </strong>During immediate recall, participants recalled one fewer word per trial in the Cannabis + Alcohol Post-Use condition compared to the other conditions (p <.001). This effect was stronger in females (p =.003). During long delay recall, participants recalled 1.5 fewer words in both Post-Use conditions compared to both Pre-Use conditions. No sex differences emerged for delayed recall trials.</p><p><strong>Conclusions: </strong>Legal-market cannabis was associated with acute verbal learning and memory impairments compared to alcohol alone, with females showing heightened vulnerability during initial encoding. Results highlight the risks of alcohol and cannabis co-use and underscore the importance of studying high-THC cannabis.</p><p><strong>Clinical trials registration: </strong>identifier NCT04998006.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing effects of isoliquiritigenin, a naturally occurring GABA_B receptor agonist, on alcohol-motivated behaviors in alcohol-preferring rats.","authors":"Paola Maccioni, Laura Regonini Somenzi, Mauro A M Carai, Federico Corelli, Gian Luigi Gessa, Giancarlo Colombo","doi":"10.1007/s00213-025-06892-x","DOIUrl":"https://doi.org/10.1007/s00213-025-06892-x","url":null,"abstract":"<p><strong>Rationale and objectives: </strong>Glycyrrhiza glabra L. (Fabaceae; licorice) is a widely used medicinal herb known to exert protective effects against multiple neurological diseases. The flavonoid, isoliquiritigenin (ISL), is a main constituent of roots of Glycyrrhiza glabra. ISL has been reported to behave as a GABA_B receptor agonist and exert multiple pharmacological effects. Given the role of the GABA_B receptor in the neurobiological and pharmacological bases of alcohol use disorder, the present study investigated the effect of ISL on a series of alcohol-related behaviors in selectively bred, female Sardinian alcohol-preferring rats.</p><p><strong>Methods and results: </strong>The collected results indicated that acute treatment with ISL (5-20 mg/kg, i.p.; 50-200 mg/kg, i.g.) decreased operant oral alcohol self-administration under both fixed and progressive ratio schedules of reinforcement and suppressed cue-induced reinstatement of alcohol seeking. ISL effect on alcohol self-administration was partially blocked by pretreatment with the GABA_B receptor antagonist, SCH50911, and potentiated by co-administration of the positive allosteric modulator of the GABA_B receptor, GS39783. Acute treatment with doses of ISL as high as 80 mg/kg (i.p.) did not alter spontaneous locomotor activity, suggestive of the specificity of ISL effects on alcohol-related behaviors.</p><p><strong>Conclusions: </strong>These results confirm the ability of ISL to behave in vivo as a GABA_B receptor agonist; they also indicate that ISL reproduced the suppressing effects of the prototypic GABA_B receptor agonist, baclofen, on multiple alcohol-related behaviors in rodents.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopamine modulation of aggression.","authors":"Bing Dai, Dayu Lin","doi":"10.1007/s00213-025-06893-w","DOIUrl":"https://doi.org/10.1007/s00213-025-06893-w","url":null,"abstract":"<p><strong>Rationale: </strong>Aggression is an innate social behavior prevalent across animal species. However, in modern human society, inter-personal aggression is considered disruptive and detrimental to both families and communities. Clinically, antipsychotics, which primarily target dopamine (DA) receptors, have been widely used to suppress hyper-aggression. However, the mechanisms underlying the effect of the antipsychotics remain incompletely understood.</p><p><strong>Objectives: </strong>We reviewed key steps in brain DA synthesis and summarized genetic and pharmacological evidence supporting the role of the mesolimbic DA system in aggression. Next, we discussed recent circuit studies that elucidate the DA action in modulating aggression-related brain regions. These lines of evidence collectively suggest that DA acts on different brain regions to facilitate aggression and self-learning, and signals the valence of the fighting experience.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lamotrigine is not associated with differential clinical outcomes in a real-world sample of patients with unipolar depression receiving ketamine or esketamine.","authors":"Mia C Santucci, Rachel B Katz, Brian Pittman, Sina Nikayin, Samuel T Wilkinson","doi":"10.1007/s00213-025-06896-7","DOIUrl":"https://doi.org/10.1007/s00213-025-06896-7","url":null,"abstract":"<p><strong>Rationale: </strong>Ketamine has emerged as a rapid-acting antidepressant. Lamotrigine is used as an off-label treatment for major depressive disorder. Some theorize, based on mechanism, that lamotrigine might interfere with ketamine's antidepressant effects.</p><p><strong>Objectives: </strong>To report on clinical outcomes for patients with depression treated concomitantly with/without lamotrigine and ketamine/esketamine.</p><p><strong>Methods: </strong>Clinical outcomes based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology-Self Report (QIDS) were organized from patients with major depressive disorder treated with ketamine/esketamine at Yale Psychiatric Hospital from 2014 through November 2023. Patients were treated with intravenous ketamine (0.5 mg/kg over 40 min) or intranasal esketamine (56 or 84 mg) twice per week for two to four weeks.</p><p><strong>Results: </strong>Overall, 347 patients with depression were treated with ketamine/esketamine, 57 of which were concurrently taking lamotrigine during the treatment period. Most (207/347, 59.7%) patients were women, with an average age of 45.6 (standard deviation [SD] = 16.6). The average dose of lamotrigine was 210.1 (SD = 153.9). In the initial, unadjusted model, there was no group (lamotrigine v. no lamotrigine) by time interaction using the MADRS (F_2,345=1.19, p = 0.30) or QIDS (F_2,338=0.51, p = 0.60) as outcomes. Adjusting for concomitant medications (antidepressants, benzodiazepines), prior exposure to electroconvulsive therapy, sex, age, race, history of psychiatric hospitalization, additional psychiatric comorbidities, and whether patients started treatment as an outpatient or inpatient did not affect results.</p><p><strong>Conclusions: </strong>We found no clinical evidence for an interaction between lamotrigine and treatment with ketamine/esketamine in a real-world sample of treatment-seeking patients with major depressive disorder.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glutamatergic Mechanisms Underlying the Antidepressant-Like Effects of 1-(Phenylselanyl)-2-(p-tolyl)indolizine in Mice.","authors":"Marcia Juciele da Rocha, Marcelo Heinemann Presa, Narryman Pinto Zuge, Kauane Nayara Bahr Ledebuhr, Carolina Aires de Oliveira, Eder João Lenardão, Filipe Penteado, Cristiani Folharini Bortolatto, César Augusto Brüning","doi":"10.1007/s00213-025-06906-8","DOIUrl":"https://doi.org/10.1007/s00213-025-06906-8","url":null,"abstract":"<p><strong>Rationale: </strong>1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with antidepressant-like properties, modulating monoaminergic system in mice. The mechanisms underlying the antidepressant effects of MeSeI have not been fully elucidated.</p><p><strong>Objectives: </strong>Considering the important role that the glutamatergic system plays in the pathophysiology of depression, this study aimed to investigate the involvement of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors signaling in the antidepressant-like effects of MeSeI in forced swimming test (FST) in mice.</p><p><strong>Methods: </strong>For this purpose, Swiss male mice were pretreated with differents antagonists or agonists; 15-30 min later, MeSeI was administered via the intragastric (i.g.) route. After an additional 30 min, mouse behavior was evaluated using the FST.</p><p><strong>Results: </strong>The antidepressant-like effects of MeSeI (50 mg/kg, i.g. route) in the FST were prevented by the pre-treatment with an NMDA receptor agonist (NMDA, 0.1 pmol/site, intracerebroventricular [i.c.v.] route) and a glycine-site NMDA receptor agonist (D-serine, 30 µg/site, i.c.v. route). Co-administration of sub-effective doses of NMDA receptor antagonists (ketamine, 0.01 mg/kg, intraperitoneal [i.p.] route and MK-801, 0.001 mg/kg, i.p. route) with a sub-effective dose of MeSeI (0.5 mg/kg, i.g. route) exerted a synergistic antidepressant-like effect in the FST in mice. However, the results show that the pre-treatment of mice with arcaine (1 mg/kg, i.p. route) or 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX, 2.5 µg/site, i.c.v. route) was not able to prevent the antidepressant-like effect of MeSeI (50 mg/kg, i.g. route) in the FST.</p><p><strong>Conclusions: </strong>Taken together, our data suggest that NMDA receptor signaling plays a role in the antidepressant-like effects of MeSeI in mice.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Social cognition in young adults who endorse a cannabis use disorder.","authors":"Gabrielle Abbott, Lisa-Marie Greenwood, Jessica G Bartschi, Suraya Dunsford, Isabella Goodwin, Anastasia Paloubis, Marianna Quinones-Valera, Eugene McTavish, Antonio Verdejo-Garcia, Janna Cousijn, Gary C K Chan, Nadia Solowij, Valentina Lorenzetti","doi":"10.1007/s00213-025-06890-z","DOIUrl":"https://doi.org/10.1007/s00213-025-06890-z","url":null,"abstract":"<p><strong>Rationale: </strong>Cannabis use disorder (CUD) affects over 50 million people globally. Emerging evidence shows that some people with CUD may experience altered social cognition (e.g., emotion recognition or differentiation). These impairments can affect their ability to understand others' emotional states and navigate social interactions, potentially contributing to chronic cannabis use, even when it leads to interpersonal problems. However, the literature on social cognition in cannabis users is inconsistent, based on a paucity of studies, and characterised by methodological issues including conflation of remitted and current CUD (i.e., does not consider abstinence effects on cognition), limited assessment of cannabis metrics (e.g., dosage) and confounds entrenched with CUD (e.g., nicotine/alcohol use, anxiety).</p><p><strong>Objectives/methods: </strong>We aimed to examine social cognition (i.e., emotion recognition and differentiation, immediate/delayed face memory) in relation to endorsement of CUD (n = 83) vs. controls (n = 32), and measures of level of problematic cannabis use (i.e., Cannabis Use Disorder Identification Test - Revised; CUDIT-R) and dosage (i.e., cannabis grams/past month), accounting for hours since last cannabis use, nicotine/alcohol use, and trait anxiety.</p><p><strong>Results: </strong>There were no significant effects of CUD (d = 0-0.314) or dosage and level of problematic cannabis use on social cognition.</p><p><strong>Conclusions: </strong>Altered social cognition may not be a key feature of CUD, or the relationship between CUD and cognition may be moderated by factors such as age, treatment seeking, education, and IQ. In this study, younger age and higher education or IQ may have served as protective factors against social alterations. Replication studies are required to validate this notion.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in compulsive alcohol drinking phenotypes: implications for decision-making and social behavior in a preclinical model.","authors":"Manuela Olmedo-Córdoba, José Juan León, Álvaro López-Villegas, Elena Martín-González, Margarita Moreno-Montoya","doi":"10.1007/s00213-025-06895-8","DOIUrl":"https://doi.org/10.1007/s00213-025-06895-8","url":null,"abstract":"<p><strong>Rationale: </strong>Compulsivity is increasingly recognized as a transdiagnostic trait that amplifies vulnerability to alcohol use disorders. However, its specific role in shaping social behavior and decision-making remains underexplored.</p><p><strong>Objective: </strong>This study aimed to identify a vulnerable phenotype characterized by compulsive alcohol drinking and evaluate its behavioral alterations within the social behavior and cognitive processes domains of the Research Domain Criteria (RDoC), considering sex as a modulatory factor.</p><p><strong>Methods: </strong>Male and female Wistar rats were exposed to Schedule-Induced Polydipsia (SIP), first with water and then with alcohol. Distinct groups were formed based on intake patterns following a cluster-based analysis. We then assessed social subordination with the social dominance tube test (SDTT), sociability and social novelty with the three-chambered Crawley's test (3CT), and decision-making with the rodent Gambling Task (rGT).</p><p><strong>Results: </strong>We identified four distinct behavioral profiles: Low Compulsive, Compulsive Alcohol, Compulsive Water, and High Compulsive. This segmentation revealed sex-specific distributions: males were overrepresented in high alcohol consumption clusters, while females were more prevalent in low-consumption profiles, indicating sex-related susceptibility. The High Compulsive phenotype diverged from the Compulsive Alcohol group, showing lower hierarchical status and a less risky decision-making strategy, whereas no significant differences were found in overall social interaction between groups. However, general alcohol consumption diminished general sociability and abolished sex differences, suggesting a disruption of innate social motivation.</p><p><strong>Conclusions: </strong>These findings support that the combination of compulsivity and alcohol intake increases behavioral vulnerability, specifically in domains of social competence and decision-making.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Behavioral variation across multiple phases of intravenous cocaine self-administration among genetically diverse mouse populations.","authors":"Price E Dickson, Udita Datta, Troy D Wilcox, Ashley A Auth, Robyn L Ball, Matt Dunn, Heidi S Fisher, Alyssa Klein, Michael R Leonardo, Tyler A Roy, Michael C Saul, Jason A Bubier, Leona H Gagnon, Vivek M Philip, Lisa M Tarantino, James D Jentsch, Elissa J Chesler","doi":"10.1007/s00213-025-06904-w","DOIUrl":"https://doi.org/10.1007/s00213-025-06904-w","url":null,"abstract":"<p><p>Genetic and other predisposing factors can influence the progression from initiation of drug intake to compulsive substance use through distinct biobehavioral processes. Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations - 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J: DO) population and their eight founder strains - to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J: DO phenotypic values exceeding the range of founders including the C57BL/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits. Together, these findings demonstrate the utility of extended self-administration protocols in high-diversity mouse populations and establish feasibility for their use in the discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemogenetic activation of the medial prefrontal cortex alleviates the impaired extinction of fear memory through the increase in the binding of EGR1 and TET1 in an animal model of PTSD.","authors":"Sho Fujita, Manabu Fuchikami, Satoshi Fujita, Tatsuhiro Miyagi, Satoshi Okada, Jun Omura, Shigeru Morinobu","doi":"10.1007/s00213-025-06891-y","DOIUrl":"https://doi.org/10.1007/s00213-025-06891-y","url":null,"abstract":"<p><strong>Rationale: </strong>Impaired extinction of fear memory (EFM) is one of the principal symptoms of posttraumatic stress disorder (PTSD). We recently reported that chemogenetic activation (CA) of the infralimbic cortex (ILC) during extinction training did not reduce fear instantly but rather facilitated later extinction retrieval in a single prolonged stress (SPS) rats, an animal model of PTSD.</p><p><strong>Objective: </strong>We examined the mechanism by which CA alleviates the impaired EFM in SPS rats.</p><p><strong>Methods: </strong>We measured protein levels of Early Growth Response 1 (EGR1) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) by western blotting, levels of binding of these two proteins by co-immunoprecipitation and western blotting, and levels of 5-hydroxymethylcytosine (5hmC), an indicator of DNA demethylation, by ELISA. Bobcat339 was used as a selective TET inhibitor, and EFM was evaluated using extinction training and extinction testing following contextual fear conditioning.</p><p><strong>Results: </strong>CA of the ILC increased the binding of EGR1 and TET1 and increased the 5hmc level in the prefrontal cortex. Administration of Bobcat339 inhibited the 5hmc increase and the alleviation of impaired EFM by the CA of the ILC in SPS rats. The extinction training was indispensable for the increased binding of EGR1 and TET1 and the alleviation of impaired EFM in response to the CA of the ILC.</p><p><strong>Conclusion: </strong>Our results suggest that CA alleviates the impaired EFM via the increase in EGR1-TET1 binding in SPS rats. Pharmacotherapy promoting DNA demethylation through the activation of the TET1 cascade may be pivotal in the treatment of PTSD.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}