Neuropsychopharmacology最新文献

{"title":"Brain structural correlates of an impending initial major depressive episode.","authors":"Anna Kraus, Katharina Dohm, Tiana Borgers, Janik Goltermann, Dominik Grotegerd, Alexandra Winter, Katharina Thiel, Kira Flinkenflügel, Navid Schürmeyer, Tim Hahn, Simon Langer, Tilo Kircher, Igor Nenadić, Benjamin Straube, Hamidreza Jamalabadi, Nina Alexander, Andreas Jansen, Frederike Stein, Katharina Brosch, Paula Usemann, Lea Teutenberg, Florian Thomas-Odenthal, Susanne Meinert, Udo Dannlowski","doi":"10.1038/s41386-025-02075-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02075-6","url":null,"abstract":"<p><p>Neuroimaging research has yet to elucidate whether reported gray matter volume (GMV) alterations in major depressive disorder (MDD) exist already before the onset of the first episode. Recruitment of presently healthy individuals with a subsequent transition to MDD (converters) is extremely challenging but crucial to gain insights into neurobiological vulnerability. Hence, we compared converters to patients with MDD and sustained healthy controls (HC) to distinguish pre-existing neurobiological markers from those emerging later in the course of depression. Combining two clinical cohorts (n = 1709), voxel-based morphometry was utilized to analyze GMV of n = 45 converters, n = 748 patients with MDD, and n = 916 HC in a region-of-interest approach and exploratory whole-brain. By contrasting the subgroups and considering both remission state and reported recurrence at a 2-year clinical follow-up, we stepwise disentangled effects of (1) vulnerability, (2) the acute depressive state, and (3) an initial vs. a recurrent episode. Analyses revealed higher amygdala GMV in converters relative to HC (p_tfce-FWE = 0.037, d = 0.447) and patients (p_tfce-FWE = 0.005, d = 0.508), remaining significant when compared to remitted patients with imminent recurrence. Lower GMV in the dorsolateral prefrontal cortex (p_tfce-FWE < 0.001, d = 0.188) and insula (p_tfce-FWE = 0.010, d = 0.186) emerged in patients relative to HC but not to converters, driven by patients with acute MDD. By examining one of the largest available converter samples in psychiatric neuroimaging, this study allowed a first determination of neural markers for an impending initial depressive episode. Our findings suggest a temporary vulnerability, which in combination with other common risk factors might facilitate prediction and in turn improve prevention of depression.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic profiling of cannabis use and cannabis intoxication in humans.","authors":"Francisco Madrid-Gambin, Noemí Haro, Natasha L Mason, Pablo Mallaroni, Eef L Theunissen, Stefan W Toennes, Oscar J Pozo, Johannes G Ramaekers","doi":"10.1038/s41386-025-02082-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02082-7","url":null,"abstract":"<p><p>Acute intoxication from Δ9-tetrahydrocannabinol (THC, the primary active ingredient of cannabis) can lead to neurocognitive impairment and interference with day-to-day operations, such as driving. Present evaluations of THC-induced impairment in legal settings rely on biological drug tests that solely establish cannabis use, rather than cannabis impairment. The current study evaluated the metabolome in blood collected from occasional and chronic cannabis users (N = 35) at baseline and following treatments with cannabis (300 μg/kg THC) and placebo, with the aim to identify unique metabolic alterations that are associated with acute cannabis intoxication and cannabis use frequency. Blood samples were collected at baseline and repeatedly during 70 min after treatment. Sustained attention performance and ratings of subjective high were taken twice within 40 min after treatment. Metabolomic fingerprints of occasional and chronic cannabis users were distinctly different at baseline, when both groups were not intoxicated. A total of 14 metabolites, mainly related to endocannabinoid and amino acid metabolism, were identified that distinguished chronic from occasional cannabis users and that yielded a discriminant analysis model with an 80% classification rate (95% CI: 61-91%). Distinct metabolomic fingerprints were found for occasional cannabis users who, in contrast to chronic cannabis users, showed attentional impairment and elevated ratings of subjective high during cannabis intoxication. These included increments in organic acids, β-hydroxybutyrate and second messenger ceramides. The current study demonstrates the feasibility of the metabolomics approach to identify metabolic changes that are specific to the neurocognitive state of cannabis intoxication and to the history of cannabis use.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal heroin self-administration in rats increases drug-seeking behavior in male offspring via miR-19b downregulation in the nucleus accumbens.","authors":"Wenjing Gao, Tingting Wang, Jian Cui, Nan Huang, Guangyuan Fan, Tao Pan, Changyou Jiang, Feifei Wang, Xing Liu, Lan Ma, Qiumin Le","doi":"10.1038/s41386-025-02081-8","DOIUrl":"https://doi.org/10.1038/s41386-025-02081-8","url":null,"abstract":"<p><p>Accumulating evidence indicates that drug addiction may lead to adaptive behavioral changes in offspring, potentially due to epigenetic modifications in parental germline. However, the underlying mechanisms remain inadequately understood. In this study, we show that paternal heroin self-administration (SA) increased heroin-seeking behavior in the F1 generation, when compared with offspring sired by yoke-infused control males, indicating cross-generational impact of paternal voluntary heroin seeking behavior. Notably, the increase of heroin seeking behavior in offspring was replicated by zygotic microinjection of sperm RNAs derived from sperm of heroin-SA-experienced rats. Analysis of non-coding RNAs in spermatozoa revealed coordinated changes in miRNA content between the nucleus accumbens and spermatozoa. We validated that restoration of miR-19b downregulation in sperm RNA from self-administration-experienced rats, in parallel with its overexpression in the nucleus accumbens of F1 offspring sired by heroin-SA-experienced fathers, reversed the increased heroin SA observed in these F1 offspring. Taken together, our findings suggest in rats that paternal heroin self-administration induces epigenetic changes in both brain and sperm miRNA, with miR-19b downregulation playing a critical role in mediating the epigenetic inheritance of increased heroin self-administration behavior in the F1 generation.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IN MEMORIAM: Floyd E. Bloom, M.D.","authors":"Gary Aston-Jones, Stephen L Foote, John H Morrison","doi":"10.1038/s41386-025-02069-4","DOIUrl":"https://doi.org/10.1038/s41386-025-02069-4","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent brain network signatures in psychosis: implications for diagnosis, prognosis, and treatment.","authors":"Elvisha Dhamala, Jose M Rubio","doi":"10.1038/s41386-025-02079-2","DOIUrl":"https://doi.org/10.1038/s41386-025-02079-2","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new module in the drug development process: preclinical multi-center randomized controlled trial of R-ketamine on alcohol relapse.","authors":"Marcus W Meinhardt, Ivan Skorodumov, Jérôme Jeanblanc, Federica Benvenuti, Fahd François Hilal, Esi Domi, Camille André, Sandra Bodeau, Virginie Jeanblanc, Kevin Domanegg, Roberto Ciccocioppo, Mickael Naassila, Rainer Spanagel","doi":"10.1038/s41386-025-02071-w","DOIUrl":"10.1038/s41386-025-02071-w","url":null,"abstract":"<p><p>The drug development process in psychiatry faces significant challenges due to low reproducibility rates in animal testing, which often leads to translation failures. To address this issue, we introduce a new approach in psychiatric drug development: a preclinical randomized controlled trial (preRCT). To demonstrate its potential utility, we conducted a multi-center preRCT using the alcohol deprivation effect (ADE) model to assess the impact of ketamine and R-ketamine on alcohol relapse across three European research centers. Ketamine (20 mg/kg) significantly reduced relapse, while R-ketamine showed efficacy only in females. A higher dose of R-ketamine (40 mg/kg) was also effective in males. These sex-dependent effects were linked to plasma R-ketamine levels, which were two-fold higher in female compared to male rats. Notably, R-ketamine demonstrated a lasting reduction in alcohol consumption without adverse effects. In conclusion, our preRCT demonstrates R-ketamine's effectiveness in reducing alcohol relapse and supports translation to a clinical RCT that accounts for sex-dependent effects.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central Executive Network drives delta-9-tetrahydrocannabinol (THC)-induced nonlinear changes in large-scale functional connectivity in adolescent nonhuman primates.","authors":"Andrew Jin Soo Byun, Harshawardhan U Deshpande, Jessi Stover, Brian D Kangas, Stephen J Kohut","doi":"10.1038/s41386-025-02068-5","DOIUrl":"10.1038/s41386-025-02068-5","url":null,"abstract":"<p><p>Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default mode (DMN), central executive (CEN), and salience networks (SN), are critically involved in vulnerability to deficits in cognitive processing often associated with adolescent cannabis use. The present study aimed to elucidate the effects of chronic THC exposure on functional connectivity (FC) of these putative large-scale networks in nonhuman primates. Separate groups of adolescent squirrel monkeys (aged 2.0-yrs [female] and 2.5-yrs [male]) were administered intramuscular injections of vehicle or THC daily (0.32 or 3.2mg/kg) for 6-months during adolescence. Resting state functional connectivity from scans conducted in awake subjects was measured before dosing, at 6-months of chronic dosing, and 60-days following discontinuation of daily THC exposure. Utilizing two distinct analytical methodologies, we observed a non-linear, dosage-dependent alteration in DMN-CEN FC across scan intervals. Specifically, exposure to a low THC dosage increased FC during chronic exposure compared to both the pre-dosing and discontinuation periods. This pattern, however, was not observed in either the vehicle or high THC dosage groups. Dual-regression unveiled a similar non-linear effect within the CEN, but not DMN, suggesting the effect on DMN-CEN FC may be driven by modifications within the CEN. Taken together, these results suggest adolescent THC exposure differentially affects large-scale brain networks and contributes to a nuanced understanding of CEN's role in disrupting brain connectivity following chronic THC exposure.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A projection from the medial prefrontal cortex to the lateral septum modulates coping behavior on the shock-probe test.","authors":"Jing Liu, Kayla M Tabisola, David A Morilak","doi":"10.1038/s41386-025-02074-7","DOIUrl":"https://doi.org/10.1038/s41386-025-02074-7","url":null,"abstract":"<p><p>Effective coping plays an important role in preventing stress-induced neuropsychiatric conditions. The ventromedial prefrontal cortex (vmPFC) has been associated with active, adaptive coping in humans and rodents. Chronic or severe stress has been shown to induce a maladaptive shift from active to passive coping behavior; however, the neural circuits for effective coping strategies remain unclear. In the current study, we demonstrated that neurons in the infralimbic (IL) subregion of rat vmPFC that project to the lateral septum (LS) were recruited by exposure to the shock probe in the shock-probe defensive burying (SPDB) test. Both chemogenetic inhibition of LS-projecting neurons in the IL and optogenetic inhibition of glutamatergic IL terminals in the LS selectively suppressed active burying responses in the SPDB test in non-stressed rats. In contrast, chemogenetic activation of the IL-LS pathway effectively reversed the shift from active coping to passive immobility in the SPDB test induced by chronic unpredictable stress (CUS). These results indicate that top-down regulation of the LS by a projection from the IL cortex is necessary for an active, adaptive behavioral coping response, and is sufficient to restore active coping that has been compromised by chronic stress. More broadly, these results point to the IL-to-LS circuit as a potential substrate underlying maladaptive shifts from active to passive coping behavior that are often associated with stress-related neuropsychiatric disorders.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crosstalk between CREB and PER2 mediates the transition between mania- and depression-like behavior.","authors":"Xin-Ling Wang, Yan-Bin Ji, Su-Xia Li, Tsvetan Serchov","doi":"10.1038/s41386-025-02076-5","DOIUrl":"https://doi.org/10.1038/s41386-025-02076-5","url":null,"abstract":"<p><p>Bipolar disorder (BD) is a severe psychiatric disorder characterized by alternating manic and depressive episodes. The molecular mechanisms underlying the transition between mania and depression remain unclear. Utilizing a mania animal model induced by ouabain, we observed reduced phosphorylated level of cyclic AMP-responsive element-binding protein (pCREB) and Period (PER)2 expression in the cornu ammonis (CA1) region of the hippocampus, which were restored by lithium treatment. shRNA knockdown of CREB or Per2 in CA1 region induced mania-like behavior, while overexpression of both factors resulted in depression-like behavior. Furthermore, our protein analyses revealed that the upregulation or downregulation of CREB or Per2 influenced each other's expression. Co-immunoprecipitation results demonstrated that CREB interacts with PER2. Taken together, our data suggest for potential inter-regulatory crosstalk between CREB-PER2 in hippocampal CA1 region, which mediates the transition between mania- and depression-like behaviors.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological reduction of reverse-translated hippocampal hyperactivity in mouse: relevance for psychosis.","authors":"Filip P Dybowski, Daniel S Scott, Carol A Tamminga","doi":"10.1038/s41386-025-02077-4","DOIUrl":"10.1038/s41386-025-02077-4","url":null,"abstract":"<p><p>Hippocampal hyperactivity (HH) is a potential biomarker in schizophrenia psychosis, which also appears in several other brain disorders, compromising specificity. We hypothesized that the reversal of HH in an established, reverse-translational animal preparation, coupled with a behavioral marker of psychosis may be a predictor of antipsychotic efficacy of a medication. We used a chemogenetic reverse-translational mouse preparation relevant to schizophrenia psychosis which shows HH and aberrant psychosis-relevant behaviors, specifically disrupted social recognition memory (SRM). Mice with and without HH were treated with three drugs; two known antipsychotics and one HH-reducing anticonvulsant, to assess their effects on both HH and SRM performance. All animals received one of the four treatments: vehicle (N = 15-24), haloperidol (N = 8-15), xanomeline (N = 8-13) or levetiracetam (N = 6-15) and were subsequently tested for baseline c-Fos protein expression within the hippocampal subfields (CA3 and CA1) as a measure of neuronal activity, or tested with the SRM task as a measure of social memory. All three drugs acutely reduced baseline HH compared to vehicle treatment. Subacute administration of haloperidol or xanomeline, the two drugs known to have antipsychotic activity, but not levetiracetam, normalized the SRM behavior to control levels. These results suggest that the reversal of HH alone cannot be a predictor of antipsychotic efficacy of an experimental drug and HH as a biomarker could benefit from a more sensitive readout approach.</p>","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}