Neuropsychopharmacology最新文献

{"title":"GABAergic neurons in the ventrolateral periaqueductal gray mediate fentanyl withdrawal and self-administration in mice","authors":"Yueyi Chen, Xi Cheng, Yue Cao, Tiange Xiao, Alexander A. Chubykin, Adam Kimbrough","doi":"10.1038/s41386-026-02457-4","DOIUrl":"10.1038/s41386-026-02457-4","url":null,"abstract":"Opioid addiction is characterized by compulsive drug seeking and use, accompanied by pain and heightened pain sensitivity (hyperalgesia) during withdrawal, yet the underlying neural mechanisms remain incompletely understood, especially for fentanyl. Using whole-brain Fos mapping and network analysis, we found that the periaqueductal gray is a central hub brain region engaged during fentanyl withdrawal, suggesting a prominent role for this region in withdrawal-associated neural signaling and warranting further examination. The ventrolateral periaqueductal gray (vlPAG) is a key site for nociceptive processing and shows robust neuronal responses during opioid withdrawal, but the role of its GABAergic neurons in fentanyl withdrawal has not been defined, and their contribution to the self-administration of drugs has not been investigated. We combined behavioral, molecular, electrophysiological, and chemogenetic approaches to examine the role of GABAergic vlPAG neurons during fentanyl withdrawal, and their contribution to withdrawal-induced hyperalgesia and fentanyl intake. During withdrawal from fentanyl, we observed increased Fos expression in GABAergic vlPAG neurons and enhanced inhibitory synaptic transmission revealed by channelrhodopsin-assisted circuit mapping, indicating increased GABAergic neuronal activity and inhibitory synaptic activity due to fentanyl use and withdrawal. Chemogenetic inhibition of GABAergic vlPAG neurons alleviated withdrawal-induced hyperalgesia. Male control mice exhibited overall escalating fentanyl self-administration across the final four intravenous self-administration sessions, whereas this escalation was not observed in males whose GABAergic vlPAG neurons were inhibited. Female mice did not exhibit a comparable effect. Together, these findings demonstrate that GABAergic vlPAG neurons are recruited during fentanyl withdrawal and contribute to withdrawal-associated nociceptive hypersensitivity. In addition, modulation of this population affects fentanyl self-administration in a sex-dependent manner. Targeting inhibitory signaling within the vlPAG may represent a strategy to alleviate withdrawal-associated hyperalgesia and limit fentanyl use.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2184-2196"},"PeriodicalIF":7.6,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02457-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148177493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of subcortical brain tissue iron as an indicator of dopamine neurophysiology in adolescent cannabis use","authors":"Sarah A. Thomas, Meghan A. Gonsalves, Gillian LeBlanc, Elizabeth Lorenc, Jane Metrik, Michael Frank, Sarah Ryan, Emily Olenik, Leslie Brick, Anthony Spirito, Jodi Gilman","doi":"10.1038/s41386-026-02444-9","DOIUrl":"10.1038/s41386-026-02444-9","url":null,"abstract":"Approximately 10–20% of U.S. adolescents report past-year cannabis use (CU). Although regular CU beginning in adolescence is expected to blunt dopamine-related neurophysiology, this hypothesis has not been tested in adolescents due to methodological limitations. However, neurophysiology contributing to dopamine can be noninvasively indexed via subcortical tissue iron measured with magnetic resonance imaging (MRI). We examined adolescent CU quantity, frequency, and problems in relation to tissue iron in regions with high dopamine activity, hypothesizing that greater CU would be linked to less tissue iron. Adolescents (n = 81; 64.2% female) aged 14–17 reporting either fewer than 5 lifetime cannabis episodes (n = 47) or more than 11 episodes (n = 34), with limited alcohol and nicotine use and no other illicit substance use, completed substance use assessments and an MRI. We calculated the inverse of the normalized T2* measurement (1/nT2*; lower values indicate less tissue iron) from resting-state functional scans by assessing relative T2* decay. 1/nT2* was estimated using subcortical masks for hypothesized regions. Lower 1/nT2* signal was associated with increased daily concentrate hits (b = –0.01, p < 0.001), cannabis hours high (b = –0.01, p = 0.016), CU frequency (b = -0.01, p = 0.01), and cannabis use disorder (CUD) severity (b = –0.01, p = 0.003). Post-hoc analyses highlighted the VTA as a key region. Results align with reduced dopamine-related neurophysiology associated with CU in adult and animal samples, and have implications for understanding adolescent CUD development. Measuring 1/nT2* offers an innovative, non-invasive method to index neurobiological alterations in adolescent CU.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2152-2162"},"PeriodicalIF":7.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02444-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148153096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Amygdala reactivity to threat, negative facial perception, and risk of future psychiatric hospitalizations: a longitudinal study in major depressive and bipolar disorders","authors":"Kamilla W. Miskowiak, Brice Ozenne, Hanne L. Kjærstad, Patrick M. Fisher, Emily E. Beaman, Vibeke H. Dam, Alexander T. Ysbæk-Nielsen, Gitte M. Knudsen, Lars V. Kessing, Julian Macoveanu, Vibe G. Frøkjær, Anjali Sankar","doi":"10.1038/s41386-026-02446-7","DOIUrl":"10.1038/s41386-026-02446-7","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 9","pages":"1742-1742"},"PeriodicalIF":7.6,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02446-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148153099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the impact of maternal oxycodone self-administration during gestation in a translational model","authors":"Eduardo R. Butelman, Yuefeng Huang","doi":"10.1038/s41386-026-02449-4","DOIUrl":"10.1038/s41386-026-02449-4","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 9","pages":"1527-1528"},"PeriodicalIF":7.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148146049","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":"Rapid and reliable computational markers of decision-making for predicting daily smoking behavior and smoking cessation treatment outcomes","authors":"Jeung-Hyun Lee, Sang Ho Lee, Jaeyeong Yang, Hyeonjin Kim, Mark A. Pitt, Hyung Jun Park, Hee-Kyung Joh, Anna B. Konova, Woo-Young Ahn","doi":"10.1038/s41386-026-02448-5","DOIUrl":"10.1038/s41386-026-02448-5","url":null,"abstract":"Addiction involves rapidly fluctuating affective and value-based decision-making processes that undermine cessation efforts, yet capturing these dynamics at clinically meaningful timescales remains challenging. Standard cognitive decision-making tasks are time-intensive and require many trials to achieve reliable parameter estimates, limiting their use longitudinally and in real-world settings. Here, we developed a rapid, smartphone-based framework that integrates ecological momentary assessment (EMA) with adaptive design optimization (ADO), a Bayesian method that enables reliable estimation of computational decision-making parameters from as few as 20-30 trials per task. We tested this framework in N = 79 individuals undergoing a 5-6-week smoking cessation program, who completed daily ADO-based delay discounting and risk/ambiguity tasks alongside EMA surveys assessing smoking behavior, craving, stress, mood, anxiety, and medication adherence. At the day-to-day level, elevated craving, depressive symptoms, and ambiguity tolerance predicted increased smoking the following day, whereas lower discounting rates and reduced craving and stress predicted cessation success at treatment completion. For the latter, models using data from the first week achieved meaningful predictive performance (mean AUC = 0.76), approaching the upper-bound performance observed in models incorporating both task and survey data from the full study period (mean AUC = 0.83). Together, these findings demonstrate that rapid, low-burden, ADO-based delivery of decision-making tasks via EMA can capture clinically relevant, dynamic vulnerability states during smoking cessation treatment. This methodology offers a promising approach for identifying cognitive markers that may facilitate or inhibit cessation success and informing personalized, time-sensitive intervention strategies for nicotine addiction and related psychiatric disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1-10"},"PeriodicalIF":7.6,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02448-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148059420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allele-specific expression in the brain links genetic risk and cortical thinning in psychiatric disorders","authors":"Nirmala Akula, Siyuan Liu, Shrey Shah, Teja Nikhil Peddada, Heejong Sung, Armin Raznahan, Francis J. McMahon","doi":"10.1038/s41386-026-02439-6","DOIUrl":"10.1038/s41386-026-02439-6","url":null,"abstract":"Allele-specific expression (ASE), where genetic variants exert dynamic control over gene expression, is not well studied in major psychiatric disorders. Here, we used transcriptome analysis in postmortem brain to identify genes with ASE, quantify differences in ASE in Schizophrenia (SCZ), Bipolar Disorder (BD), and Major Depressive Disorder (MDD), and explore regional relationships between differential ASE (dASE) and cortical thickness. Genome-wide analysis of ASE was performed by comparing RNA-sequencing read ratios of parental alleles in subgenual anterior cingulate cortex (sgACC) from 185 individuals with SCZ, BD, MDD, or no psychiatric disorder. ASE was detected by read-back phasing using phASER. dASE between cases and controls was performed using ASEP, a mixed model that accounts for sample information and correlation among SNPs. Heritability enrichment was calculated using linkage disequilibrium score regression. The Allen human brain atlas was used to map regional expression of dASE genes, which were compared with regional neuroanatomical changes reported in psychiatric patients. Of all 11,234 genes considered, 27% showed ASE at FDR < 0.05. Partitioned heritability analysis showed that ASE SNPs accounted for 13–16% of the heritability of MDD, BD and SCZ (enrichment p < 0.001). ASE SNPs significantly (p < 0.001) overlapped with GWAS variants in SCZ (odds ratio (OR) = 3.15), BD (OR = 2) and MDD (OR = 1.52). At FDR < 0.05, 1871 genes showed dASE in one or more diagnostic groups. These genes were enriched for regions with neuropsychiatric copy number variants (CNVs) and for several brain-relevant functional categories, especially those related to synapses. Expression of genes with dASE was increased in brain regions previously reported to show cortical thinning in patients with psychiatric disorders. This is the first study to explore the role of ASE in 3 major adult psychiatric disorders. We show that ASE is widespread in sgACC, that ASE SNPs contribute disproportionately to psychiatric disease heritability, dASE genes cluster in genomic regions with known neuropsychiatric CNVs and are most highly expressed in brain regions reported to show cortical thinning in psychiatric patients. Taken together, these findings highlight the importance of ASE in psychiatric disease risk and suggest that dysregulation of gene expression contributes to thinning of the cerebral cortex associated with psychiatric disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1916-1923"},"PeriodicalIF":7.6,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148045445","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 vulnerability to heroin relapse after more than one year of abstinence in rats","authors":"Rajtarun Madangopal, Olivia R. Drake, Diana Q. Pham, Veronica A. Lennon, Sophia J. Weber, Justine Lee, Adekemi Sobukunola, Ava R. Holmes, Omodolapo Nurudeen, Yavin Shaham, Bruce T. Hope","doi":"10.1038/s41386-026-02447-6","DOIUrl":"10.1038/s41386-026-02447-6","url":null,"abstract":"Relapse to opioid use during abstinence is often triggered by drug-associated cues but the persistence of this effect during prolonged abstinence is unknown. Using a rat model, we found that relapse provoked by heroin-predictive discriminative stimuli persisted for over one year of abstinence, suggesting enduring, potentially lifelong opioid relapse vulnerability.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 8","pages":"1519-1523"},"PeriodicalIF":7.6,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148039184","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":"Psilocybin modulates social behaviour in male and female mice in a time-dependent manner","authors":"Sheida Shadani, Kaspar McCoy, Lina Ong, Erika Greaves, Kyna Conn, Zane B. Andrews, Claire J. Foldi","doi":"10.1038/s41386-026-02450-x","DOIUrl":"10.1038/s41386-026-02450-x","url":null,"abstract":"With the resurgence of psychedelic research and growing evidence of their therapeutic potential, there is an urgent need to understand how these compounds act across biological sexes. Despite widespread interest in their use for conditions marked by social impairments, including depression, anxiety, and anorexia nervosa, the influence of sex as a biological variable on the prosocial effects of psychedelics remains poorly understood. Indeed, enhanced connectedness, sociability and empathy are common outcomes of psychedelic use and these have shaped human social structures for millennia. Here, we investigated the sex-specific effects of a single dose of psilocybin (1.5 mg/kg) in C57BL/6 J mice across multiple aspects of social behaviour. Psilocybin acutely enhanced huddling and induced hypothermia selectively in female mice and post-acutely (4 h) enhanced novelty-seeking and grooming in females, with no comparable effects in males. By 24 h, psilocybin-treated males showed reduced grooming and rearing alongside increased sociability directed toward a cage-mate. This was accompanied by blunted novelty-evoked nucleus accumbens dopamine responses that persisted to 7 days post-administration. At 7 days, psilocybin shifted female social preference toward familiarity over novelty, associated with prolonged nucleus accumbens dopamine release during familiar conspecific interactions, while males exhibited increased grooming, opposing the effect observed at 24 h. Both 5-HT1AR and 5-HT2AR contributed to psilocybin’s behavioural effects in sex-specific ways. These findings reveal temporally dynamic, sex-differentiated patterns of social behaviour and dopaminergic modulation following psilocybin, underscoring the importance of sex-informed approaches in preclinical research and clinical application of psychedelic compounds.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 9","pages":"1588-1598"},"PeriodicalIF":7.6,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02450-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconciling hippocampal semantic representations of traumatic memory in PTSD","authors":"Daniela Schiller, Ofer Perl, Or Duek, Ifat levy, Ilan Harpaz-Rotem","doi":"10.1038/s41386-026-02451-w","DOIUrl":"10.1038/s41386-026-02451-w","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 8","pages":"1524-1525"},"PeriodicalIF":7.6,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008512","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":"Resting-state functional connectivity of the default mode network as a predictor for escitalopram response in adolescents with depression","authors":"Moonyoung Jang, Kyung Hwa Lee, Jiyoon Shin, Jung Lee, Jae Hyun Yoo, Jeeyoung Chun, Jisung Ahn, Jae-Won Kim","doi":"10.1038/s41386-026-02442-x","DOIUrl":"10.1038/s41386-026-02442-x","url":null,"abstract":"Adolescent depression differs from adult depression in neurobiology and treatment response. Although resting-state functional connectivity (rsFC) of the default mode network (DMN) has been linked to treatment response in adults, its value as a biomarker in adolescents remains unclear. This study investigated whether baseline DMN rsFC predicts response to selective serotonin reuptake inhibitor (SSRI) treatment in adolescents with major depressive disorder (MDD). Seventy medication-naïve adolescents with MDD (ages 12-17 years) underwent baseline resting-state functional magnetic resonance imaging and an 8-week open-label escitalopram trial. Depressive symptoms were measured using the Children’s Depression Rating Scale-Revised (CDRS-R). Seed-based DMN rsFC analyses used the ventromedial prefrontal cortex (vMPFC), dorsomedial prefrontal cortex (dMPFC), and posterior cingulate cortex (PCC) as seeds. Voxel-wise regressions assessed associations between baseline rsFC and treatment response, defined as the change in CDRS-R score from baseline to week 8. Our results showed that greater baseline DMN rsFC consistently predicted SSRI treatment response in adolescents with MDD. Stronger vMPFC-postcentral gyrus, vMPFC-insula, dMPFC-supramarginal, and PCC-supramarginal gyrus rsFCs at baseline were significantly associated with greater treatment response, as reflected by greater reductions in CDRS-R score following escitalopram treatment (r = -0.498 to -0.603, all ps < 0.001). However, rsFCs within the DMN did not predict SSRI treatment response (all ps > 0.05). These findings suggest that baseline rsFC between DMN hubs and regions in the sensorimotor and frontoparietal networks may serve as a biomarker of SSRI treatment response in adolescents with depression. This could support individualized treatment strategies within precision psychiatry for youth with MDD.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2037-2044"},"PeriodicalIF":7.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02442-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}