Neuropsychopharmacology最新文献

{"title":"Anoctamin 2 deletion alters dopamine-related signaling and impairs inhibitory behavioral control in mice","authors":"Eunsil Cho, Jooeun Bae, Jae Gwang Song, Joeun Seo, Seung-Hae Kwon, Eun Mi Hwang, Young Hoon Sung, Hyung Wook Kim, Jae-Yong Park","doi":"10.1038/s41386-026-02525-9","DOIUrl":"10.1038/s41386-026-02525-9","url":null,"abstract":"Anoctamin 2 (ANO2, TMEM16B) is a calcium-activated chloride channel best known for its role in sensory neurons, yet its expression in multiple brain regions associated with dopamine-related signaling, including the prefrontal cortex, striatum, substantia nigra, ventral tegmental area, and cerebellum, suggests broader functions in central neural circuits. However, the contribution of ANO2 to dopamine-related neural function and behavior remains undefined. To address this question, we generated ANO2-deficient mice using CRISPR–Cas9–mediated gene editing and examined their behavioral and neurochemical phenotypes. ANO2 knockout mice exhibited age-dependent hyperactivity, impaired inhibitory behavioral control, altered aversive/risk-related responses, and selective motor coordination deficits, while spatial learning and memory were preserved. Neurochemically, ANO2 deficiency resulted in reduced tyrosine hydroxylase expression and phosphorylation, decreased dopamine levels despite unchanged dopamine transporter expression, region- and subtype-dependent dopamine receptor alterations, and reduced downstream signaling markers across cortico–striatal and cerebellar circuits. These changes suggest impaired dopamine biosynthesis and altered dopamine-related signaling rather than broad disruption of dopaminergic neuronal identity. Together, these findings identify ANO2 as a potential modulator of dopamine-related signaling and inhibitory behavioral control, expanding current understanding of calcium-activated chloride channel function in neural circuits relevant to behavioral domains implicated in neuropsychiatric disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2258-2268"},"PeriodicalIF":7.6,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805247","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 neuropsychopharmacology of treatment discontinuation","authors":"Baeksun Kim","doi":"10.1038/s41386-026-02518-8","DOIUrl":"10.1038/s41386-026-02518-8","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1911-1913"},"PeriodicalIF":7.6,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02518-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148709382","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":"A non-neuronal fMRI signal: both a confound and an opportunity for insight","authors":"Amy C. Janes, Cole Korponay, Tianye Zhai, Blaise B. Frederick","doi":"10.1038/s41386-026-02512-0","DOIUrl":"10.1038/s41386-026-02512-0","url":null,"abstract":"Functional magnetic resonance imaging (fMRI) is widely used to investigate brain function. However, interpretation of the blood oxygen level-dependent (BOLD) signal is complicated by the fact that it reflects both neuronal activity and vascular physiology. This problem is especially relevant in neuropsychopharmacology research because pharmacological and psychiatric effects on brain function are often accompanied by physiological shifts. Here, we discuss recent evidence for an approach to disentangling neuronal and physiological components of the BOLD signal that enhances the interpretability and clinical utility of fMRI. Converging findings suggest that the systemic low-frequency oscillation (sLFO), a major component of the global signal, indexes cardiovascular manifestations of arousal rather than neuronal function. As such, retaining the sLFO in fMRI data can substantially distort functional connectivity estimates, leading to the misinterpretation of physiological fluctuations in arousal as neuronal effects. At the same time, the sLFO itself tracks physiological arousal level, behavioral performance, drug craving, pharmacological modulation, and large-scale brain network organization. Collectively, we suggest that when interpreting fMRI data, sLFO-indexed physiological arousal should both be modeled and considered separately, as extracting this signal from fMRI data provides dual benefits: a cleaner neuronal signal and a complementary index of behaviorally relevant physiology.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1914-1915"},"PeriodicalIF":7.6,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02512-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674912","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":"Cool but not harmless: synthetic cooling agents enhance nicotine reinforcement via the mesolimbic dopamine system","authors":"Mary Amir Bishara, Giordano de Guglielmo","doi":"10.1038/s41386-026-02503-1","DOIUrl":"10.1038/s41386-026-02503-1","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1746-1747"},"PeriodicalIF":7.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02503-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582096","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":"Synthetic cooling agents enhance nicotine reinforcement and mesolimbic dopamine signaling","authors":"Sarah K. Maddox, Esther N. Mensah, Lauren E. Young, Hannah D. Strcula, Shane V. Perelman, M. Kyle Sword, Brandon J. Henderson","doi":"10.1038/s41386-026-02485-0","DOIUrl":"10.1038/s41386-026-02485-0","url":null,"abstract":"Flavor additives in electronic delivery systems (ENDS) have been shown to enhance nicotine reinforcement. Although some states and cities have pursued implementation of menthol bans, synthetic coolants such as WS-3 and WS-23 have emerged as substitutes. In this study, we investigated the impact of WS-3 and WS-23 on nicotine self-administration behavior and dopamine (DA) release in the nucleus accumbens (NAc) core. To model nicotine reinforcement, we used an E-Vape® self-administration (EVSA) assay and observed that male and female mice exposed to nicotine plus WS-3 and WS-23 exhibited enhanced self-administration behavior when compared to mice exposed to nicotine alone or PGVG (control treatment). We also observed that the enhancement in nicotine self-administration is similar to what is observed with menthol. To measure changes in dopamine release, we used fast-scan cyclic voltammetry (FSCV) and fiber photometry. Here, we observed that WS-3 and WS-23 increased the amount of dopamine released in the NAc under both tonic (5 Hz) and phasic (60 Hz) stimulation conditions when compared with nicotine-alone. Fiber photometry recordings showed that the WS-3 and WS-23 enhanced nicotine-stimulated dopamine release in the NAc core. Using electrophysiology and microscopy assays, we observed that synthetic coolants enhance the intrinsic excitability of ventral tegmental area (VTA) dopamine neurons and enhance nicotine-induced upregulation of nicotinic acetylcholine receptors (nAChRs). In both FSCV and photometry assays, synthetic coolants produced enhancements in dopamine signaling that were comparable in magnitude to those observed with menthol. These findings demonstrate that synthetic cooling agents enhance nicotine reinforcement and are associated with increased mesolimbic dopamine signaling, enhanced VTA dopamine neuron excitability, and increased nicotine-induced nAChR upregulation.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1748-1757"},"PeriodicalIF":7.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02485-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582104","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":"Cortisol suppression impairs retrieval of emotional memory and changes its neural correlates immediately and four days post-treatment","authors":"Despina Antypa, Patrik Vuilleumier, Ulrike Rimmele","doi":"10.1038/s41386-026-02505-z","DOIUrl":"10.1038/s41386-026-02505-z","url":null,"abstract":"Emotional memories are hard to forget. Yet, past research showed that very high and very low levels of the stress hormone cortisol crucially affect the retrieval of emotional memories both immediately and in a long-lasting manner. With a double-blind, placebo-controlled, within-subject fMRI design involving humans, the present study investigated the acute and lasting effects of cortisol suppression on the neural memory representations for emotional events. The pharmacological suppression of the physiological morning cortisol rise impaired immediate memory retrieval and disrupted the involvement of key brain regions, but also persistently altered the neural memory representations for these emotional memories, tested four days later. These results indicate that cortisol suppression distorts the engagement of the emotional memory neural network and is linked to lasting changes in emotional memory representations, suggesting potential for future research on clinical strategies for attenuating distressing emotional memories.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"1991-1998"},"PeriodicalIF":7.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02505-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148582074","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":"Evidence for pro-cognitive benefits of cannabinoids in people with bipolar disorder","authors":"Alannah Miranda, Breanna M. Holloway, Elizabeth Peek, Holden Rosberg, Adam L. Halberstadt, David J. Grelotti, William Perry, Jared W. Young, Arpi Minassian","doi":"10.1038/s41386-026-02489-w","DOIUrl":"10.1038/s41386-026-02489-w","url":null,"abstract":"Cannabis use is highly prevalent among people with bipolar disorder, potentially due to a desire to self-medicate against symptoms, such as racing thoughts and poor concentration. Such symptoms are associated with attention and inhibitory control deficits, functions that are regulated in-part by temporal perception. Temporal perception is impaired in BD and is slowed by acute cannabis exposure. The effects of cannabis use (CU) on temporal perception and its associated cognitive functions in people with BD remains unclear. Here, we conducted two studies to 1) test for associations between chronic CU and cognitive function (i.e., attention and inhibitory control) and temporal perception in people with BD and healthy comparison (HC) adults, and 2) investigate the impact of acute Δ9-tetrahydrocannabinol (THC) administration on such functions in a randomized clinical trial in non-CU people with BD and HC adults. Participants completed the Temporal Discrimination Task (TDT) and 5-Choice Continuous Performance Task (5C-CPT). In the chronic CU study, we observed that non-CU BD participants had significantly less precise timing compared to other groups, whereas BD + CU participants had comparable TDT performance to non-CU HC participants. Similarly, BD + CU, but not non-CU BD, participants had comparable 5C-CPT performance to non-CU HC. In the acute THC administration study, we observed faster timing in BD participants administered THC compared to placebo-treated HC participants. These data support that CU in people with BD reflect attempts to self-medicate. Future research will investigate whether cannabinoid-based treatments can remediate cognitive deficits in BD.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2132-2140"},"PeriodicalIF":7.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02489-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148552117","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":"Psilocybin produces amplified acute responses and sex-specific long-term increases in sensorimotor gating in the mGlu5 knockout mouse model of schizophrenia","authors":"James J. Gattuso, Ahmed Kamal, Jennyfer M. Payet, Kato Havaux, Jenna Hendey, Bilgenur Bezcioglu, Zoe J. Phelan, Maddy Orchard, Divyesh Bhanot, Matthew W. Hale, Anthony J. Hannan, Thibault Renoir","doi":"10.1038/s41386-026-02501-3","DOIUrl":"10.1038/s41386-026-02501-3","url":null,"abstract":"Psilocybin is a serotonergic psychedelic drug with emerging therapeutic applications, yet its actions under glutamatergic dysfunction, and relevance to schizophrenia and associated psychiatric disorders, remain unclear. We examined the acute and long-lasting effects of psilocybin (1 mg/kg, intraperitoneal) on behavioral and neural outcomes in the metabotropic glutamate receptor 5 (mGlu5) knockout (KO) mouse model of schizophrenia. The mGlu5 KO mice displayed psilocybin-induced hyperlocomotion, whereas wild-type (WT) mice did not. Additionally, male mGlu5 KO mice showed an amplified psilocybin-induced head-twitch response (HTR) compared with WT males, consistent with sex-dependent enhancement of 5-HT2A receptor-mediated signaling. Acute psilocybin increased c-Fos expression in the claustrum of WT but not KO mice, suggesting intact mGlu5 signaling is required for psilocybin-evoked claustral recruitment. Psilocybin did not alter anxiety-like behavior in the light–dark box and increased immobility time in the Porsolt test. Strikingly, psilocybin produced a sustained normalization in prepulse inhibition (a measure of sensorimotor gating) in female KO mice, evident nine days after treatment. Together, these findings indicate that disrupted mGlu5 signaling amplifies acute responses to psilocybin and reveals a sex-dependent long-term effect on sensorimotor gating. These results refine understanding of glutamatergic–serotonergic interactions and motivate further work evaluating psilocybin across schizophrenia-relevant endophenotypes.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2111-2123"},"PeriodicalIF":7.6,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41386-026-02501-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148498673","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":"Acute alcohol triggers rank-specific social ascent through a prefrontal-accumbens circuit in male mice","authors":"Xiao Jia, Hui Zhou, Can Tang, Jiale Ye, Zhiyang Yu, Jun-Li Cao, Can Li, Kunwei Wu","doi":"10.1038/s41386-026-02495-y","DOIUrl":"10.1038/s41386-026-02495-y","url":null,"abstract":"Alcohol is known to alter social behavior, yet how it acts on the brain to produce specific, rank-dependent changes in social competition remains unknown. Here we show in male mice that a low dose of alcohol induces a rapid, transient, and highly selective upward shift in social hierarchy: it promotes dominance behavior exclusively in mid-ranking animals, enabling them to stably outcompete their immediate superior. Critically, this effect was absent in both dominant and the lowest-ranking subordinates, demonstrating a precise social-context gating of alcohol’s action. This rank-specific effect is also absent in females. Using cFos mapping and chemogenetic manipulations, we identify CaMKIIα-expressing glutamatergic neurons in the prelimbic prefrontal cortex (PL) as both necessary and sufficient for this alcohol-driven social ascent. Anatomical and functional analyses reveal that alcohol selectively recruits the PL→nucleus accumbens (NAc) pathway, and projection-specific inhibition of this circuit abolishes the behavioral effect. These findings delineate a social rank–gated prefrontal–accumbal circuit that mediates the selective pro-dominance action of alcohol, providing a mechanistic basis for how a globally acting drug can produce precise, context-dependent changes in social structure.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 10","pages":"1855-1864"},"PeriodicalIF":7.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148475711","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":"Dose-related reductions in prefrontal recruitment during cognitive reappraisal following oral delta-9-tetrahydrocannabinol in posttraumatic stress disorder","authors":"Connor. J. Haggarty, Christine. A. Rabinak","doi":"10.1038/s41386-026-02502-2","DOIUrl":"10.1038/s41386-026-02502-2","url":null,"abstract":"Posttraumatic stress disorder (PTSD) is characterized by difficulties in emotion regulation and altered recruitment of prefrontal control systems during cognitive reappraisal. Cannabinoid signaling has been implicated in stress and affect regulation, yet dose-dependent effects of acute delta-9-tetrahydrocannabinol (THC) on the neural mechanisms supporting reappraisal in PTSD remain unclear. In a randomized, double-blind, placebo-controlled design, adults with PTSD received a single oral dose of placebo (N = 12), 5 mg dronabinol (synthetic THC; N = 12), or 10 mg dronabinol (N = 13) prior to fMRI during a validated cognitive reappraisal task. Relative to placebo, both THC doses were associated with reduced activation during reappraisal of negative images (Reappraise-Negative > Maintain-Negative) across prefrontal and parietal regions implicated in top-down control, with broader and stronger attenuation at 10 mg. In contrast, in-scanner negative affect ratings were robustly sensitive to task conditions but did not differ by dose. Post-scan valence and arousal ratings confirmed expected stimulus effects without reliable dose effects. Exploratory analyses revealed limited correspondence between regional activation and subjective affect. These findings indicate that acute oral THC is associated with dose-dependent reductions in recruitment of prefrontal control circuitry during cognitive reappraisal in PTSD without detectable changes in self-reported affect, consistent with a potential neural-subjective dissociation, although smaller behavioral effects may not have been detectable in the current sample.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"51 11","pages":"2141-2151"},"PeriodicalIF":7.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148475734","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}