Psychopharmacology最新文献

{"title":"The interaction between finasteride and corticosterone levels: implications for depression-, and anxiety-like behavior and hippocampal synaptic plasticity in male rats.","authors":"Jose Nayana, Byrathnahalli S Shankaranarayana Rao, Bettadapura N Srikumar","doi":"10.1007/s00213-025-06810-1","DOIUrl":"https://doi.org/10.1007/s00213-025-06810-1","url":null,"abstract":"<p><strong>Rationale: </strong>Finasteride is FDA-approved for the treatment of hair loss and in older men for benign prostatic hyperplasia. However, some patients treated with finasteride reported suicidal ideation, depression, and anxiety. The neurobiological mechanisms underlying this are not clearly understood. Previously, we showed that short-term finasteride administration results in depression- and anxiety-like behaviour. Since finasteride treatment is long-term in the clinic, we examine the effects of chronic finasteride administration in the current study.</p><p><strong>Objective: </strong>This study aims to understand the behavioral, cellular, and molecular changes in male rats following 21 days of finasteride (3 mg, 10 mg, and 30 mg/Kg) administration.</p><p><strong>Methods: </strong>Depression-like behavior was evaluated using forced swim (FST), sucrose preference (SPT), and splash tests. Anxiety-like behavior was assessed using elevated plus maze (EPM), open field (OFT), light-dark (LDT), Vogel's conflict (VCT), and home cage emergence (HCET), and depression-related anxiety in novelty-suppressed feeding task (NSFT) tests. Hippocampal synaptic plasticity was assessed by field excitatory post-synaptic potentials (fEPSP) recordings in the Schaffer-collateral-CA1 synapses, and plasma corticosterone levels were estimated using ELISA.</p><p><strong>Results: </strong>Chronic finasteride administration induced depression-like and anxiety-like behavior in SPT and EPM, respectively, but not in the other paradigms. There was a modest decrease in long-term potentiation in the hippocampus. Interestingly, there was an increase in the plasma corticosterone levels with 6 days of finasteride administration, but not after 14 or 21 days of administration.</p><p><strong>Conclusions: </strong>Chronic administration of finasteride did not induce a robust depression- and anxiety-like behavior and modestly affected synaptic plasticity. This could be potentially because of the adaptive response observed in the plasma corticosterone levels.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079709","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":"The link between tobacco smoking and susceptibility to misinformation.","authors":"Michal Piksa, Magdalena Zaniewska, Agata Cieslik-Starkiewicz, Jonas Kunst, Mikolaj Morzy, Jan Piasecki, Rafal Rygula","doi":"10.1007/s00213-025-06802-1","DOIUrl":"https://doi.org/10.1007/s00213-025-06802-1","url":null,"abstract":"<p><strong>Introduction: </strong>This study investigates the relationship between tobacco smoking and susceptibility to misinformation, an area that has been underexplored despite its potential implications for public health and media literacy. Smoking behavior, along with the pharmacological components present in tobacco, is often associated with habitual and cognitive patterns that may influence an individual's ability to critically evaluate and discern false information. By examining this potential link, the present study aims to shed light on the broader implications of smoking for societal challenges, such as the spread of misinformation.</p><p><strong>Methods: </strong>A quantitative online survey was conducted to collect data from a sample of 1,575 adult participants (M_age = 41.37, SD = 13.58; females: 54%, males: 46%) from the United Kingdom. Participants were categorized into three groups based on their smoking status: individuals who had smoked tobacco less than an hour before the study (n = 550), individuals who had smoked more than an hour before the study (n = 472), and non-smokers (n = 553). The survey incorporated questions assessing susceptibility to misinformation by annotating certain claims as false or true, and other instruments in order to control for impulsivity, stress level, physiological arousal and education level.</p><p><strong>Results: </strong>Smokers exhibited a lower ability to correctly recognize false claims than non-smokers. There was no difference between these groups in true news recognition.</p><p><strong>Discussion: </strong>The study, controlling for confounding factors, such as education and perceived stress, reveals that tobacco smoking may be associated with misinformation susceptibility. Further laboratory-based research should be conducted to explore the mechanisms underlying the observed relationship.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079710","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":"The serum levels of polyunsaturated fatty acids contribute to the antidepressant-like effects of 18β-Glycyrrhetinic acid in mice.","authors":"Wanzhao Ding, Maohua Yao, Xiaoling Liang, Winghei Wong, Wei Yao, Ji-Chun Zhang","doi":"10.1007/s00213-025-06813-y","DOIUrl":"https://doi.org/10.1007/s00213-025-06813-y","url":null,"abstract":"<p><strong>Rationale: </strong>18β-Glycyrrhetinic acid (18β-GA) exhibits antidepressant-like effects in mice, but the underlying mechanisms remain unclear.</p><p><strong>Objective: </strong>This study aimed to explore the role of serum polyunsaturated fatty acids in the antidepressant-like effects of 18β-GA.</p><p><strong>Results: </strong>18β-GA exerted antidepressant-like effects in mice susceptible to chronic social defeat stress (CSDS). These effects were associated with increased serum levels of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and N-docosahexaenoylethanolamide (DEA), alongside decreased levels of 14,15-dihydroxyeicosatrienoic acid (DHET). Additionally, 18β-GA restored the suppressed brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway and reduced the elevated pro-inflammatory cytokine levels in CSDS-susceptible mice.</p><p><strong>Conclusions: </strong>This study demonstrates that the antidepressant-like effects of 18β-GA in CSDS-susceptible mice are closely associated with DHA and its metabolites.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079787","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":"Chronic administration of methocinnamox, a mu-opioid receptor antagonist, reduces hedonic response without impacting motivation in mice.","authors":"Misbah Sheikh, Emily Cambre, Cory Langreck, Jonathan A Javitch, Sarah E Canetta","doi":"10.1007/s00213-025-06801-2","DOIUrl":"https://doi.org/10.1007/s00213-025-06801-2","url":null,"abstract":"<p><strong>Rationale: </strong>Genetic and pharmacological studies suggest that signaling through the mu opioid receptor (MOR) is essential for motivation to seek, and hedonic response to, both drugs of abuse as well as natural rewards. Given that impairments in hedonic reactivity and motivation are key behavioral features of depression, we wondered whether sustained deficits in endogenous opioid signaling in adulthood could produce these 'depression-related' behavioral phenotypes.</p><p><strong>Objectives: </strong>To investigate the effect of chronic MOR blockade in adulthood on motivation and hedonic response to a food reward, as well as whether these behavioral variables are correlated at the individual animal level.</p><p><strong>Methods: </strong>We chronically administered the pseudo-irreversible MOR antagonist methocinnamox (MCAM) for three weeks prior to assessing motivation and hedonic reactivity for a food reward in the progressive ratio and lickometer tasks, respectively. We then assessed whether motivation and hedonic response to reward were correlated at the individual animal level.</p><p><strong>Results: </strong>Chronic administration of MCAM decreased hedonic response, while leaving goal-directed motivation intact. In addition, there was a weak negative correlation between motivation and hedonic response in individual mice treated with chronic MCAM, but not control mice.</p><p><strong>Conclusions: </strong>Chronic blockade of the MOR decreases hedonic response, without impacting motivation to work for the same reward. Although the different components of reward processing such as motivation and hedonic response may be related, they appear to be dissociable.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018445","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":"A Mechanistic study assessing difficulty discontinuing chronic hypnotic use.","authors":"Timothy Roehrs, Gail Koshorek, Mohammad Sibai, Aisha Tabor, Luisa Bazan, Thomas Roth","doi":"10.1007/s00213-025-06799-7","DOIUrl":"https://doi.org/10.1007/s00213-025-06799-7","url":null,"abstract":"<p><strong>Rationale: </strong>The abuse liability of chronic hypnotic use remains a clinical concern.</p><p><strong>Objectives: </strong>This study assessed 1) whether there would be greater difficulty discontinuing chronic hypnotic use for people with insomnia and hyperarousal vs those with insomnia but without hyperarousal and 2) whether those seeking to discontinue chronic hypnotic use of the receptor non-specific hypnotic eszopiclone would have more difficulty than those discontinuing the receptor specific zolpidem XR.</p><p><strong>Methods: </strong>DSM-V diagnosed insomnia participants, aged 23-61 yrs, (n = 41, 36 females), with no other sleep disorders, unstable medical or psychiatric diseases or drug dependency completed the trial. Following a screening nocturnal polysomnogram (NPSG) participants were randomized to zolpidem XR (12.5 mg), eszopiclone (3 mg), or placebo nightly for 6 months. After 6 months nightly use, over a 2-week discontinuation, they were instructed to discontinue their hypnotic use, but, if necessary, to self-administer before sleep either 1, 2, or 3 capsules, each packaged separately in envelopes labeled 1, 2, and 3, containing their assigned \"blinded\" medication or placebo.</p><p><strong>Results: </strong>Over the 14 nights 21 participants took zero (51%) capsules and among the 20 taking capsules the median total number chosen was 3. Those people with insomnia and hyperarousal vs those with insomnia but not hyperarousal had more difficulty discontinuing chronic hypnotic use (aim 1) as did those using eszopiclone vs zolpidem or placebo (aim 2).</p><p><strong>Conclusions: </strong>Most subjects discontinued hypnotic use and among the few continuing to use their use declined from week one to week two of the discontinuation period.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028858","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":"(R)-ketamine induces mGlu₅ receptor-dependent antidepressant-like effects in the chronic unpredictable mild stress model of depression in mice.","authors":"Agnieszka Pałucha-Poniewiera, Anna Rafało-Ulińska, Agata Faron-Górecka, Paulina Pabian, Katarzyna Kaczorowska","doi":"10.1007/s00213-025-06803-0","DOIUrl":"https://doi.org/10.1007/s00213-025-06803-0","url":null,"abstract":"<p><strong>Rationale: </strong>(S)-Ketamine, which is used to treat depression, has significant undesirable effects and has potential for abuse. A safe alternative to (S)-ketamine is (R)-ketamine. The relationship between (R)-ketamine and the mGlu₅ receptor is unknown, although screening tests indicate the possibility of potentiation of the antidepressant effect of (R)-ketamine by the mGlu₅ receptor negative allosteric modulator (NAM).</p><p><strong>Objectives: </strong>We aimed to investigate whether the antidepressant-like effect of (R)-ketamine is mGlu₅ receptor-dependent. Specifically, we investigated the possibility of enhancing (R)-ketamine antidepressant-like effects using the partial mGlu₅ receptor NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), in a chronic unpredictable mild stress (CUMS) model of depression in mice.</p><p><strong>Methods: </strong>The effect of (R)-ketamine on mGlu₅ receptor availability in the mouse brain was investigated using an autoradiographic method. Animal behaviors reflecting anhedonia, apathy, and helplessness were analyzed to study the rapid and sustained antidepressant-like effects of the combined administration of (R)-ketamine and M-5MPEP. Hippocampal protein levels were measured via Western blotting.</p><p><strong>Results: </strong>(R)-Ketamine altered mGlu₅ receptor availability in several mouse brain regions. Importantly, in the hippocampus, (R)-ketamine reversed CUMS-induced effects. Behavioral studies revealed that M-5MPEP enhanced the effectiveness of a subeffective dose of (R)-ketamine. This drug combination effectively reduced CUMS-induced apathy- and anhedonia-like behavior symptoms. Changes in hippocampal eukaryotic elongation factor2 (eEF2) and tropomyosin receptor kinase B (TrkB) levels accompanied these effects.</p><p><strong>Conclusions: </strong>The weakening of mGlu₅ receptor function in the hippocampus appears to be related to the (R)-ketamine antidepressant-like effect, and coadministration of the partial mGlu₅ receptor NAM, M-5MPEP, might increase its antidepressant activity.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014375","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":"A systematic review and meta-analysis of the acute effect of caffeine on attention.","authors":"Kasper Kløve, Anders Petersen","doi":"10.1007/s00213-025-06775-1","DOIUrl":"https://doi.org/10.1007/s00213-025-06775-1","url":null,"abstract":"<p><strong>Rationale: </strong>Although there is broad agreement that caffeine provides an acute improvement in attention in the normal population, estimates of effect size vary and the relationship between dose and effect is unclear.</p><p><strong>Objective: </strong>To examine the acute effect of caffeine on attention in a systematic review and meta-analysis.</p><p><strong>Methods: </strong>PsycINFO, PubMed, and Scopus were searched for records published in English with no limits on the year of publication. Studies were included if they were randomized, double-blinded, placebo-controlled, and if they examined the acute effect of pure caffeine on behavioral tests of attention in rested, healthy adults. For every included trial, eligible outcomes were extracted and aggregated to form one composite standardized mean difference (SMD; Hedges' adjusted g) for reaction time and one for accuracy. The SMDs were then combined in random-effects meta-analyses. Additionally, several subgroup analyses were conducted, including meta-regressions on dose-response relationships.</p><p><strong>Results: </strong>Thirty-one trials with a total of 1455 participants were included in the meta-analysis. Significant effects in favor of caffeine were found for both accuracy, g = 0.27, and reaction time, g = 0.28. Subgroup analyses showed that higher doses of caffeine (≥ 200 mg) improved both reaction time and accuracy more than lower doses, but whereas a positive linear dose-response relationship was found for reaction time, a quadratic relationship was found for accuracy. The effect of caffeine was not related to differences in habitual caffeine consumption, task complexity, or which attention network was taxed.</p><p><strong>Conclusion: </strong>The current evidence shows that in the normal population, caffeine acutely enhances attention by improving both reaction time and accuracy. However, whereas higher doses continue to enhance reaction time, accuracy improves only up to a certain point before declining.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036648","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":"Depression of intracranial self-stimulation in male and female rats by intraperitoneal lactic acid: effects of morphine, ketoprofen, and interactions with G-protein biased kappa opioid agonists.","authors":"Thomas J Martin, Conner W Martin, Kevin J Frankowski, Bruce E Blough, Jeffrey Aubé, Laura M Bohn, Sara R Jones","doi":"10.1007/s00213-025-06800-3","DOIUrl":"https://doi.org/10.1007/s00213-025-06800-3","url":null,"abstract":"<p><strong>Introduction: </strong>Numerous pharmacological classes of compounds have been explored as novel and efficacious alternatives to standard mu opioid agonist analgesics. We and others have described G-protein biased kappa opioid agonists as having potential utility as analgesics due to a lower propensity to produce sedation and dysphoria, which are thought to be mediated in large part through beta-arrestin signaling.</p><p><strong>Methods: </strong>Here we compare two G-protein biased kappa agonists that differ in their basic chemical scaffold, triazole 1.1 (Tr1.1) and isoquinolinone 2.1 (Iso2.1), for alteration of intracranial self-stimulation (ICSS) in male and female rats. Lactic acid (LA) was given i.p. at a concentration sufficient to produce moderate to severe depression of ICSS.</p><p><strong>Results: </strong>Neither Tr1.1 nor Iso2.2 reversed the effects of lactic acid at concentrations that produced significant depression of ICSS in either sex. Neither drug altered ICSS in the absence of lactic acid administration. In both males and females, morphine reversed the effects of i.p. lactic acid on ICSS and co-administration of Tr1.1 did not alter the dose-effect curve for morphine in either sex. Similar effects were observed for ketoprofen. Ketoprofen also reversed the effects of i.p. lactic acid on ICSS in both sexes in a dose-dependent manner, and co-administration of neither Tr1.1 nor Iso2.1 altered the ketoprofen dose-effect curve.</p><p><strong>Conclusions: </strong>These data suggest that these G-protein biased kappa agonists may lack sufficient efficacy or potency to alter the effects of opioids or NSAIDs against moderate to severe antinociceptive stimuli in rats, and development of more potent or efficacious compounds may be required to demonstrate efficacy in rat models of moderate to severe nociception.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144051059","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":"Oleoylethanolamide restores stress-induced prepulse inhibition deficits and modulates inflammatory signaling in a sex-dependent manner.","authors":"Macarena González-Portilla, Sandra Montagud-Romero, Fernando Rodríguez de Fonseca, Marta Rodríguez-Arias","doi":"10.1007/s00213-023-06403-w","DOIUrl":"10.1007/s00213-023-06403-w","url":null,"abstract":"<p><strong>Rationale: </strong>Social stress contributes to the development of depressive and anxiety symptomatology and promotes pro-inflammatory signaling in the central nervous system. In this study, we explored the effects of a lipid messenger with anti-inflammatory properties - oleoylethanolamide (OEA) - on the behavioral deficits caused by social stress in both male and female mice.</p><p><strong>Methods: </strong>Adult mice were assigned to an experimental group according to the stress condition (control or stress) and treatment (vehicle or OEA, 10 mg/kg, i.p.). Male mice in the stress condition underwent a protocol consisting of four social defeat (SD) encounters. In the case of female mice, we employed a procedure of vicarious SD. After the stress protocol resumed, anxiety, depressive-like behavior, social interaction, and prepulse inhibition (PPI) were assessed. In addition, we characterized the stress-induced inflammatory profile by measuring IL-6 and CX3CL1 levels in the striatum and hippocampus.</p><p><strong>Results: </strong>Our results showed that both SD and VSD induced behavioral alterations. We found that OEA treatment restored PPI deficits in socially defeated mice. Also, OEA affected differently stress-induced anxiety and depressive-like behavior in male and female mice. Biochemical analyses showed that both male and female stressed mice showed increased levels of IL-6 in the striatum compared to control mice. Similarly, VSD female mice exhibited increased striatal CX3CL1 levels. These neuroinflammation-associated signals were not affected by OEA treatment.</p><p><strong>Conclusions: </strong>In summary, our results confirm that SD and VSD induced behavioral deficits together with inflammatory signaling in the striatum and hippocampus. We observed that OEA treatment reverses stress-induced PPI alterations in male and female mice. These data suggest that OEA can exert a buffering effect on stress-related sensorimotor gating behavioral processing.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"913-928"},"PeriodicalIF":3.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9982986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia.","authors":"E J Marijke Achterberg, Barbara Biemans, Louk J M J Vanderschuren","doi":"10.1007/s00213-024-06559-z","DOIUrl":"10.1007/s00213-024-06559-z","url":null,"abstract":"<p><strong>Rationale: </strong>Genetic and environmental factors cause neuropsychiatric disorders through complex interactions that are far from understood. Loss-of-function mutations in synaptic proteins like neurexin1α have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), both characterised by problems in social behaviour. Childhood social play behaviour is thought to facilitate social development, and lack of social play may precipitate or exacerbate ASD and SCZ.</p><p><strong>Objective: </strong>To test the hypothesis that an environmental insult acts on top of genetic vulnerability to precipitate psychiatric-like phenotypes. To that aim, social behaviour in neurexin1α knockout rats was assessed, with or without deprivation of juvenile social play. We also tested drugs prescribed in ASD or SCZ to assess the relevance of this dual-hit model for these disorders.</p><p><strong>Results: </strong>Neurexin1α knockout rats showed an aberrant social phenotype, with high amounts of social play, increased motivation to play, age-inappropriate sexual mounting, and an increase in general activity. Play deprivation subtly altered later social behaviour, but did not affect the phenotype of neurexin1α knockout rats. Risperidone and methylphenidate decreased play behaviour in both wild-type and knockout rats. Amphetamine-induced hyperactivity was exaggerated in neurexin1α knockout rats.</p><p><strong>Conclusion: </strong>Deletion of the neurexin1α gene in rats causes exaggerated social play, which is not modified by social play deprivation. This phenotype therefore resembles disinhibited behaviour rather than the social withdrawal seen in ASD and SCZ. The neurexin1α knockout rat could be a model for inappropriate or disinhibited social behaviour seen in childhood mental disorders.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"1069-1089"},"PeriodicalIF":3.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12043747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}