Neuropsychopharmacology最新文献

{"title":"Extended amygdala corticotropin-releasing hormone neurons regulate sexually dimorphic changes in pair bond formation following social defeat in prairie voles (Microtus ochrogaster)","authors":"Maria C. Tickerhoof, Lina K. Nerio Morales, Jeff Goff, Erika M. Vitale, Adam S. Smith","doi":"10.1038/s41386-025-02067-6","DOIUrl":"10.1038/s41386-025-02067-6","url":null,"abstract":"The neurobiological mechanisms underlying the connection between anxiety brought on by social stressors and the negative impact on relationship formation have remained elusive. In order to address this question, we used the social defeat model in the socially monogamous prairie vole to investigate the impact of this stress on pair bond formation. Social defeat experience inhibited partner preference formation in males but promoted preference in females. Furthermore, pair bonding increased corticotropin-releasing hormone (CRH) expression in the bed nucleus of the stria terminalis (BNST) in male prairie voles, while defeat experience increased BNST CRH expression in females. Chemogenetic excitation of BNST CRH neurons during a short cohabitation with a new partner promoted a partner preference in stress-naïve prairie voles. Interestingly, chemogenetic inhibition of BNST CRH neurons during cohabitation with a new partner blocked partner preference in stress-naïve males but promoted preference in defeated males. Inhibition of BNST CRH neurons also blocked partner preference in stress-naïve females but did not alter preference behavior in defeated females. This study revealed sexual dimorphism in not only the impact of social defeat on pair bond formation, but also in the role BNST CRHergic neurons play in regulating changes in pair bonding following social conflict.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"965-975"},"PeriodicalIF":6.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409390","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 molecular mechanism mediating clozapine-enhanced sensorimotor gating","authors":"Ioannis Mantas, Ivana Flais, Niclas Branzell, Tudor M. Ionescu, Eugene Kim, Xiaoqun Zhang, Diana Cash, Bastian Hengerer, Per Svenningsson","doi":"10.1038/s41386-025-02060-z","DOIUrl":"10.1038/s41386-025-02060-z","url":null,"abstract":"The atypical antipsychotic clozapine targets multiple receptor systems beyond the dopaminergic pathway and influences prepulse inhibition (PPI), a critical translational measure of sensorimotor gating. Since PPI is modulated by atypical antipsychotics such as risperidone and clozapine, we hypothesized that p11—an adaptor protein associated with anxiety- and depressive-like behaviors and G-protein-coupled receptor function—might modulate these effects. In this study, we assessed the role of p11 in clozapine’s PPI-enhancing effect by testing wild-type and global p11 knockout (KO) mice in response to haloperidol, risperidone, and clozapine. We also performed structural and functional brain imaging. Contrary to our expectation that anxiety-like p11-KO mice would exhibit an augmented startle response and heightened sensitivity to clozapine, PPI tests showed that p11-KO mice were unresponsive to the PPI-enhancing effects of risperidone and clozapine. Imaging revealed distinct regional brain volume differences and reduced hippocampal connectivity in p11-KO mice, with significantly blunted clozapine-induced connectivity changes in the CA1 region. Our findings highlight a novel role for p11 in modulating clozapine’s effects on sensorimotor gating and hippocampal connectivity, offering new insight into its functional pathways.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"721-730"},"PeriodicalIF":6.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02060-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399576","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":"Absence of TAAR1 function increases methamphetamine-induced excitability of dorsal raphe serotonin neurons and drives binge-level methamphetamine intake","authors":"Samantha M. Rios, John R. K. Mootz, Tamara J. Phillips, Susan L. Ingram","doi":"10.1038/s41386-025-02063-w","DOIUrl":"10.1038/s41386-025-02063-w","url":null,"abstract":"Methamphetamine (MA) is a potent psychostimulant capable of exerting both rewarding and aversive effects, the balance of which likely drives variation in voluntary MA intake. Understanding the genetic factors underlying sensitivity to these effects of MA is critical for developing effective treatments. The activity of dorsal raphe serotonin neurons is linked to reward processing. Here, we performed whole-cell patch-clamp electrophysiology in dorsal raphe serotonin neurons from mice with high or low MA intake corresponding with high or low MA reward sensitivity. The MA drinking (MADR) mice consist of the MA reward sensitive MA high drinking (MAHDR) and the MA reward insensitive MA low drinking (MALDR) lines. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and MAHDR mice are homozygous for a mutation in the Taar1 gene, Taar1m1J, that encodes non-functional TAAR1, whereas MALDR mice possess at least one copy of the reference Taar1+ allele that encodes functional TAAR1. Our previous research using CRISPR-Cas9-generated MAHDR-Taar1+/+ knock-in mice in which Taar1m1J was replaced with Taar1+, and non-edited MAHDR-Taar1m1J/m1J controls demonstrated that lack of TAAR1 function is critical for heightened MA consumption and MA reward sensitivity. Here, electrophysiological recordings in the MADR lines demonstrate a MA-induced decrease in dorsal raphe serotonin neuron activity from MALDR, but not MAHDR mice. However, in the presence of serotonin autoreceptor antagonists, MA potentiates dorsal raphe serotonin neuron activity of MAHDR, but not MALDR mice. Importantly, potentiation in the presence of the antagonists is abolished in knock-in mice expressing functional TAAR1. The knock-in mice did not display binge-level MA intake, consistent with the loss of MA-reward sensitivity previously reported in mice with functional TAAR1. Finally, because MA is a substrate of the serotonin transporter, we evaluated whether the serotonin transporter is necessary for MA-induced potentiation of dorsal raphe serotonin neuron activity in mice with non-functional TAAR1. The serotonin transporter antagonist fluoxetine blocks MA-induced potentiation for both MAHDR and MAHDR-Taar1m1J/m1J mice. Thus, TAAR1 function directly impacts MA reward sensitivity and MA intake and serves as a critical regulator of MA-induced activity of dorsal raphe serotonin neurons through its interaction with the serotonin transporter.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 7","pages":"1136-1144"},"PeriodicalIF":6.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02063-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399651","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":"Brain and cardiovascular responses to acute stress in remitted and recurrent late-life depression","authors":"Thomas E. Kraynak, Helmet T. Karim, Layla Banihashemi, Robert T. Krafty, Meryl A. Butters, Olusola A. Ajilore, Warren D. Taylor, Carmen Andreescu","doi":"10.1038/s41386-025-02057-8","DOIUrl":"10.1038/s41386-025-02057-8","url":null,"abstract":"In individuals with remitted late-life depression (LLD), stress exposure can increase the likelihood of a new, recurrent depressive episode. Variability in the effect of stress on recurrence risk may reflect underlying brain and physiological processes mediating the stress response. We examined how subjective, physiological, and brain responses to an experimental stressor differs in older adults with and without remitted depression, and how these stress responses relate to future relapse. Participants were recruited through 3 sites and included 76 older adults with remitted LLD and 36 age-matched healthy comparison (HC) adults. Participants completed an acute stressor task during functional brain imaging with behavioral and cardiovascular monitoring. Remitted LLD participants were followed longitudinally to evaluate depression recurrence. Compared to HC, the remitted LLD group exhibited reduced stressor-evoked systolic blood pressure and heart rate responses, as well as reduced stressor-evoked posterior insula activity. This blunted stress response phenotype appeared more specific to the stable remitter group than the relapsing LLD group. Survival analyses demonstrated that greater stressor-evoked bed nucleus of the stria terminalis (BNST) activity was associated with faster time to recurrence. These findings add to a growing literature reporting so-called “blunted” stressor-evoked cardiovascular and brain reactivity in remitted depression. Moreover, they link the stress response in visceral interoceptive brain circuits with relapse vulnerability. Future work involving longer follow-up periods may reveal additional stress-related brain and behavioral predictors of recurrence in remitted LLD.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"956-964"},"PeriodicalIF":6.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365020","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":"N-acetylcysteine for youth cannabis use disorder: randomized controlled trial main findings","authors":"Kevin M. Gray, Rachel L. Tomko, Nathaniel L. Baker, Erin A. McClure, Aimee L. McRae-Clark, Lindsay M. Squeglia","doi":"10.1038/s41386-025-02061-y","DOIUrl":"10.1038/s41386-025-02061-y","url":null,"abstract":"Cannabis use disorder is particularly prevalent and impairing among young people, and evidence-based treatments are limited. Prior trials of N-acetylcysteine, added to contingency management as a platform behavioral intervention, yielded positive findings in youth but not in adults. This trial sought to rigorously evaluate whether N-acetylcysteine is efficacious in youth when not paired with a robust behavioral treatment platform. Treatment-seeking youth with cannabis use disorder (N = 192, ages 14–21) were randomized to receive a double-blind 12-week course of oral N-acetylcysteine 1200 mg or placebo twice daily; all received weekly medical management and brief behavioral counseling. The primary efficacy outcome was the proportion of negative urine cannabinoid tests during treatment, compared between groups. An array of self-report and urine testing measures were examined secondarily to assess cannabis use reduction and cessation outcomes. The N-acetylcysteine and placebo groups did not differ in proportion of negative urine cannabinoid tests (RR = 0.93, 95% CI = 0.53, 1.64; p = 0.80) or self-reported cannabis abstinence (RR = 1.02, 95% CI = 0.63, 1.65; p = 0.93) during treatment. The mean percentage of cannabis use days and grams of cannabis used per using day decreased over time during treatment but did not differ between groups. More N-acetylcysteine than placebo treated participants reported gastrointestinal adverse events (63/98 versus 37/94, χ21 = 11.9 p < 0.001); adverse events were otherwise similar between groups. Findings indicate that N-acetylcysteine is not efficacious for youth cannabis use disorder when not paired with contingency management, highlighting the potentially crucial role of a robust behavioral treatment platform in facilitating prior positive efficacy findings with N-acetylcysteine. Trial Registration: Clinicaltrials.gov identifier NCT03055377","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"731-738"},"PeriodicalIF":6.6,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02061-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256127","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: Neuropsychopharmacology Volume 50 Issue 2","authors":"","doi":"10.1038/s41386-025-02056-9","DOIUrl":"10.1038/s41386-025-02056-9","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"1-1"},"PeriodicalIF":6.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02056-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633147","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":"Childhood family environment and μ-opioid receptor availability in vivo in adulthood","authors":"Aino Saarinen, Lauri Tuominen, Sampsa Puttonen, Olli Raitakari, Liisa Keltikangas-Järvinen, Jarmo Hietala","doi":"10.1038/s41386-025-02059-6","DOIUrl":"10.1038/s41386-025-02059-6","url":null,"abstract":"Animal studies have reported associations of early maternal separation with altered μ-opioid receptor function but data on humans are scarce. We now investigated whether childhood family environment is related to μ-opioid receptor availability in the human brain in adulthood. Healthy participants (n = 37–39 in the analyses) were recruited from the prospective population-based Young Finns Study (YFS) that started in 1980. Childhood family environment was evaluated in 1980, including scores for stress-prone life events, disadvantageous emotional family atmosphere, and adverse socioeconomic environment. We used positron emission tomography (PET) with radioligand [11C]carfentanil to measure μ–opioid receptor availability in adulthood. Age- and sex-adjusted analyses showed that exposure to stress-prone life events in childhood was related to lower μ-opioid receptor binding in the orbitofrontal cortex, hippocampus, putamen, amygdala, insula, thalamus, anterior cingulate cortex, and dorsal caudate in adulthood (when compared to participants not exposed to stress-prone life events). Unfavorable socioeconomic family environment or disadvantageous emotional family atmosphere was not associated with μ-opioid receptor availability in adulthood. In conclusion, exposure to environmental instability (i.e., to stress-prone life events below traumatic threshold) during early development is associated with dysregulation of the u-opioid receptor transmission in adulthood. The findings increase understanding of the neurobiological mechanisms involved in the associations between childhood adversities and adulthood mental disorders.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 7","pages":"1130-1135"},"PeriodicalIF":6.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02059-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075173","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":"Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes?","authors":"Lauren M. Osborne, Semra Etyemez, Graziano Pinna, Rebecca Alemani, Lindsay R. Standeven, Xin-Qun Wang, Jennifer L. Payne","doi":"10.1038/s41386-025-02052-z","DOIUrl":"10.1038/s41386-025-02052-z","url":null,"abstract":"Postpartum depression (PPD) affects ~10–15% of childbearing individuals, with deleterious consequences for two generations. Recent research has explored the biological mechanisms of PPD, particularly neuroactive steroids (NAS). We sought here to investigate associations between NAS levels and ratios during pregnancy and the subsequent development of depressive symptoms with postpartum onset. NAS levels and psychological scales were measured in individuals with and without mood disorders at up to eight visits across pregnancy and postpartum. Generalized linear mixed-effects regression models were used to assess relationships in euthymic pregnant individuals between each of the NAS biomarkers and ratios and subsequent PPD. Participants with a one-unit increase in the log isoallopregnanolone/pregnanolone ratio at the third trimester (T3) had higher odds (OR = 1.64, 95% CI: 1.13–2.37, FDR adjusted p = 0.038, C-index = 0.82), and those with a one-unit increase in the log pregnanolone/progesterone ratio at T3 had lower odds (OR = 0.64, 95% CI: 0.47–0.88, FDR adjusted p = 0.036, C-index = 0.82) of developing PPD; those with a one-unit increase in the log progesterone level at T3 had higher odds of developing PPD (OR = 4.00, 95% CI: 1.54–10.37, FDR adjusted p = 0.035, C-index = 0.80). We found key differences in the progesterone metabolic pathway at the third trimester, indicating likely decreased activity/expression of the 3α-HSD enzyme and/or increased activity/expression of 3β-HSD.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 6","pages":"904-912"},"PeriodicalIF":6.6,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066128","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":"Correction: Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study","authors":"Ryan Terry-Lorenzo, Daniel Albrecht, Sabrinia Crouch, Richard Wong, Gordon Loewen, Nagdeep Giri, Heather Skor, Kelly Lin, Christine M. Sandiego, Meghan Pajonas, Eugenii A. Rabiner, Roger N. Gunn, David S. Russell, Dietrich Haubenberger","doi":"10.1038/s41386-025-02055-w","DOIUrl":"10.1038/s41386-025-02055-w","url":null,"abstract":"","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 4","pages":"719-719"},"PeriodicalIF":6.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024214","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":"Endocannabinoid contributions to the perception of socially relevant, affective touch in humans","authors":"Madeleine R. Jones, Connor J. Haggarty, Gavin N. Petrie, Abigail R. Lunge, India Morrison, Matthew N. Hill, Markus Heilig, Leah M. Mayo","doi":"10.1038/s41386-025-02053-y","DOIUrl":"10.1038/s41386-025-02053-y","url":null,"abstract":"Social relationships are central to well-being. A subgroup of afferent nerve fibers, C-tactile (CT) afferents, are primed to respond to affective, socially relevant touch and may mitigate the effects of stress. The endocannabinoid ligand anandamide (AEA) modulates both social reward and stress. We thus hypothesized that AEA levels would be associated with the perceived pleasantness of affective touch in humans. Across two studies, we explored perceptions of affective, socially relevant touch and general affective stimuli. In study 1, adult participants (N = 101) were recruited based on presence (CM+) or absence (CM−) of documented childhood maltreatment (N = 52 CM+; N = 49 CM−). In study 2, healthy individuals were randomized to receive an inhibitor of fatty acid amide hydrolase (FAAH; PF-04457845) to increase AEA levels (n = 16) or placebo (n = 29). Outcomes included self-report ratings of touch pleasantness and intensity, valence and arousal ratings of affective images, and plasma levels of endocannabinoids AEA and 2-AG, cortisol, and oxytocin. In study 1, higher AEA levels were associated with a reduced preference for affective, CT-optimal touch. In study 2, pharmacological elevation of AEA resulted in reduced preference for affective touch. These effects were specific to social processing, as AEA levels were not related to ratings of affective images. In contrast to our hypothesis, elevated AEA was associated with reduced pleasantness ratings of CT-optimal, affective touch. This provides novel, in-human data linking AEA to social processing, adding nuance to the rationale for its use as a potential novel therapeutic target in disordered in social processing.","PeriodicalId":19143,"journal":{"name":"Neuropsychopharmacology","volume":"50 5","pages":"849-855"},"PeriodicalIF":6.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41386-025-02053-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024216","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}