Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology最新文献

{"title":"Inflammatory pain in mice induces light cycle-dependent effects on sleep architecture.","authors":"Dominika J Burek, Khairunisa Mohamad Ibrahim, Andrew G Hall, Ashish Sharma, Jessica A Cucinello-Ragland, Erik S Musiek, Jose A Morón, William A Carlezon","doi":"10.1038/s41386-025-02152-w","DOIUrl":"10.1038/s41386-025-02152-w","url":null,"abstract":"<p><p>Pain syndromes include physical, sensory, emotional, and cognitive symptoms such as disability, negative affect, feelings of stress, and fatigue. Experimental induction of long-term inflammatory pain in rodents by hindpaw injection of complete Freund's adjuvant (CFA) produces anhedonia and dysregulated naturalistic behaviors, similar to the effects of unregulated stress. We examined whether these similarities extend to changes in sleep and rhythms, such as those induced by chronic social defeat stress, using actigraphy and wireless EEG in mice. Comparisons were made between groups that received injections at the onset of the light or dark phase. We found that CFA-induced inflammatory pain alters sleep architecture in both sexes; most notably, it increased sleep duration in the dark phase-when mice are normally more likely to be awake-while also increasing sleep bout length and reducing wake bout length. In contrast, during the light phase, it decreased sleep bout length, indicating fragmentation. Similarly, CFA-induced increases in REM and SWS duration and bouts were largest during the dark phase. Dark-phase effects were remarkably consistent regardless of whether the mice had been injected at darkness onset or 12 h earlier, whereas light-phase effects were more dependent on time since injection. Injections also produced non-specific alterations in circadian rhythmicity. Our findings indicate that inflammatory pain prominently increases sleep during normally active phases as well as transitions between sleep and wakefulness throughout the day. These effects align with clinical observations and establish a basis for mechanistic studies and use of these procedures to better predict outcomes in humans.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling time-dependent genetic components underlying alcohol response.","authors":"Keiko Hikino, Ikuo Otsuka, Shunji Oshima, Akitoyo Hishimoto, Kouichi Ozaki, Xiaoxi Liu, Yuki Ishikawa, Taisei Mushiroda, Sachio Matsushita, Chikashi Terao","doi":"10.1038/s41386-025-02147-7","DOIUrl":"10.1038/s41386-025-02147-7","url":null,"abstract":"<p><p>While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH2*2 and ADH1B*2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype-phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The new normal: neural network adaptations in late-life depression.","authors":"Ebrahim Haroon, Andrew H Miller","doi":"10.1038/s41386-025-02145-9","DOIUrl":"10.1038/s41386-025-02145-9","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Four dimensions of individualization in brain stimulation for psychiatric disorders: context, target, dose, and timing.","authors":"Ghazaleh Soleimani, Michael A Nitsche, Colleen A Hanlon, Kelvin O Lim, Alexander Opitz, Hamed Ekhtiari","doi":"10.1038/s41386-025-02134-y","DOIUrl":"https://doi.org/10.1038/s41386-025-02134-y","url":null,"abstract":"","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144328485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Medial nucleus accumbens dopamine receptors modulate motivation for wheel running in male mice.","authors":"Naoya Nishitani, Taisuke Kokume, Harumi Taniguchi, Katsuyuki Kaneda","doi":"10.1038/s41386-025-02136-w","DOIUrl":"https://doi.org/10.1038/s41386-025-02136-w","url":null,"abstract":"<p><p>Abnormal motivation for natural rewards is a hallmark of various psychiatric disorders, including behavioral addiction. The mesolimbic dopamine pathway has been identified as a critical modulator of motivated behavior primarily based on studies using food-reinforced operant tasks. However, the focus on food rewards in previous studies limits the generalizability of these findings to other natural rewards implicated in behavioral addiction. In this study, we investigated the reinforcing and high motivational properties of wheel running in rodents by developing a wheel running-reinforced operant conditioning procedure. This procedure allowed for the independent quantification of appetitive and consummatory behaviors as operant responses and running duration, respectively, facilitating an in-depth exploration of the role of dopamine signaling in the medial nucleus accumbens (mNAc) in wheel running motivation. The results indicated that the systemic inhibition of dopamine D₁ and D₂ receptors suppressed appetitive behavior, whereas inhibition of D₁ receptors reduced consummatory behavior. Similarly, inhibition of mNAc neural activity and blockade of D₁ and D₂ receptors within this region diminished appetitive behavior, with D₁ receptor inhibition uniquely impairing consummatory behavior. Fiber photometry recordings demonstrated that decreases in mNAc neural activity and increases in dopamine levels preceded appetitive behavior. Additionally, mNAc neural activity and dopamine levels were elevated following cues signaling the availability of wheel running. Furthermore, systemic D₁ receptor inhibition attenuated the reduction in mNAc neural activity observed during appetitive behavior. These findings suggest that increased dopamine release and the subsequent D₁ receptor-mediated suppression of mNAc neural activity underlie the motivated behavior for wheel running.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neural and psychophysiological effects of cannabidiol in youth with alcohol use disorder: A randomized controlled clinical trial.","authors":"Anna E Kirkland, Brittney D Browning, Lindsay R Meredith, Elizabeth Robertson, Cori Herring, Rachel L Tomko, Kevin M Gray, Lindsay M Squeglia","doi":"10.1038/s41386-025-02141-z","DOIUrl":"10.1038/s41386-025-02141-z","url":null,"abstract":"<p><p>Novel treatment evaluation for youth with alcohol use disorder (AUD) is needed. Cannabidiol (CBD), a constituent of the Cannabis sativa plant, may be a promising candidate pharmacotherapy due to its potential therapeutic properties and preclinical research suggesting it decreases alcohol use. Due to limited data in humans, rigorous screening of the acute neural, psychophysiological, and alcohol-related effects of CBD is indicated to assess its viability as a potential treatment for youth AUD. Using a within-subjects, randomized, double-blind, placebo-controlled design, we tested acute multi-modal effects of CBD (600 mg) in non-treatment seeking youth with AUD (N = 36; ages 17-22; 69% female). Outcomes included (1) glutamate+glutamine (Glx) and GABA levels in the anterior cingulate cortex measured with proton magnetic resonance spectroscopy; (2) whole-brain and a priori region-of-interest neural alcohol cue-reactivity measured with functional MRI; (3) psychophysiological response to alcohol olfactory cues measured by self-reported acute alcohol craving, heart rate variability, and skin conductance; and (4) alcohol use. No CBD-associated adverse events were observed. There were no effects of acute CBD administration, compared to placebo, on any outcomes of interest. This is the first adequately powered medication screening study for the use of CBD in youth with AUD. We did not detect significant effects of CBD on neurometabolic, neurobehavioral, psychophysiological, or alcohol use outcomes in this sample. Future studies may benefit from chronic administration to better understand substance-related effects.Clinicaltrials.gov NCT05317546 https://clinicaltrials.gov/study/NCT05317546.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144278126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prefrontal corticotropin-releasing factor promotes resilience to social stress.","authors":"Ya-Tao Wang, Yong Li, Meng-Yun Li, Yue-Ming Zhang, Yue Wang, Qi-Qi Xu, Rong-Yu Liu, Xin-Ya Qin, Qing-Hong Shan, Yu Wang, Jiang-Ning Zhou, Peng Chen","doi":"10.1038/s41386-025-02148-6","DOIUrl":"https://doi.org/10.1038/s41386-025-02148-6","url":null,"abstract":"<p><p>Variations in individual coping styles have been linked to either resilience or vulnerability towards stress, thereby influencing the probability of developing stress-related disorders. The involvement of corticotropin-releasing factor (CRF) neurons within the medial prefrontal cortex (mPFC) plays a crucial role in modulating behavioral responses to stressful situations. In this study utilizing a mouse model of social defeat stress (SDS), we demonstrate how coordinated activation and localized release of CRF within the mPFC contribute to promoting adaptive responses under stressful conditions leading to enhanced resilience against subsequent challenges. Specifically, during SDS exposure, heightened activity levels were observed among mPFC CRF neurons coincide with increased local release triggered by active exploration and defensive behaviors, while decreased responses were detected upon exposure to aggression. Interestingly, the CRF neural activity and local release responding to coping behaviors throughout chronic social defeat stress (CSDS) differed between susceptible and resilient mice. Furthermore, activation of CRF receptor 1 (CRFR1) signaling in the mPFC enhanced active coping behaviors and conferred resilience to CSDS, while inhibition of CRF system promoted passive coping behaviors and induced susceptibility to sub-threshold SDS. Additionally, inhibition of CRFR1 in the mPFC nullified the pro-resilience effect elicited by activation of CRF neurons during CSDS. The collective findings provide evidence supporting the crucial role of local endogenous CRF derived from mPFC CRF neurons in maintaining resilience through active coping styles when confronted with social stress. Moreover, these results suggest that targeting the mPFC CRF system could hold promise as a therapeutic approach for managing stress-related disorders.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sitagliptin as a therapeutic approach for social anxiety disorder: the role of DPP4 and NPY in modulating social fear and comorbid depressive-like behavior in mice.","authors":"Iulia Zoicas, Christiane Mühle, Stephan von Hörsten, Anne-Christine Plank, Johannes Kornhuber","doi":"10.1038/s41386-025-02146-8","DOIUrl":"https://doi.org/10.1038/s41386-025-02146-8","url":null,"abstract":"<p><p>We have previously shown that neuropeptide Y (NPY) reduces social fear in an animal model that closely mimics the key behavioral symptoms of social anxiety disorder (SAD). Since NPY cannot yet be routinely administered to patients, we investigated the effects of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor approved for the treatment of type 2 diabetes mellitus, on social fear and comorbid depression in mice. In addition to its well-known effects on glucose metabolism, sitagliptin also prevents the degradation of NPY, thereby increasing its concentration in the blood and the brain. We show that sitagliptin administration via drinking water (50 and 100 mg/kg/day, for 4 weeks) not only reduced social fear but also prevented the onset of comorbid depressive-like behavior in outbred CD1 mice. A similar phenotype was observed in homozygous DPP4-deficient mice, emphasizing the role of DPP4 in regulating these behaviors. However, in NPY-deficient mice, sitagliptin showed reduced efficacy, suggesting that NPY plays an important role in mediating the effects of sitagliptin on social fear and comorbid depression. These findings have important clinical implications, indicating that early intervention with sitagliptin could be an effective strategy for treating SAD, alleviating both core symptoms and reducing the risk of developing comorbid mood disorders that often complicate treatment outcomes.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking.","authors":"Kate Z Peters, Zuzana Pedan, Romarua Agbude, Emily C Woods, Oliver G Steele, Nobuyoshi Suto, Scott B Kinghorn, Olga Tsaponina, Eisuke Koya","doi":"10.1038/s41386-025-02142-y","DOIUrl":"10.1038/s41386-025-02142-y","url":null,"abstract":"<p><p>Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or 'neuronal ensembles' in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify 'anti-craving' relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of 'originally', or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or 'excitatory overdrive'. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting 'inhibitory underdrive'. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory 'overdrive' and inhibitory 'underdrive' likely underlies EE's anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conditioned versus innate effort-based tasks reveal divergence in antidepressant effect on motivational state in male mice.","authors":"Foteini Xeni, Caterina Marangoni, Lynn Lin, Emma S J Robinson, Megan G Jackson","doi":"10.1038/s41386-025-02140-0","DOIUrl":"https://doi.org/10.1038/s41386-025-02140-0","url":null,"abstract":"<p><p>Antidepressant-induced apathy syndrome is reported in a high number of patients. It is characterised by loss of motivation for daily activities and emotional blunting. It has a negative impact on quality of life and treatment outcome, yet the changes in underlying neurobiology driving this syndrome remain unclear. To begin to address this, a comprehensive understanding of how different classes of antidepressant treatment impact on behaviours relevant to apathy is critical. Rodent motivation for reward is commonly assessed using effort-based operant conditioning paradigms such as the Effort for Reward task. However, motivation to perform spontaneous/innate behaviours may provide additional insight into changes in behaviour reflective of daily activities. We tested the acute and chronic effects of antidepressants on the Effort for Reward task, and the spontaneous/innate Effort-Based Forage task. Acute treatment revealed important divergence in drug effect between tasks, where selective serotonin reuptake inhibitor (SSRI)/serotonin and noradrenaline reuptake inhibitor (SNRI) treatment impaired foraging behaviour in the Effort Based Forage task, but enhanced high-effort, high-value reward responding in the Effort for Reward task. Treatment with a noradrenaline reuptake inhibitor (NRI) or multimodal agent impaired foraging behaviour but did not affect high reward responding in the Effort for Reward task. Conversely, chronic treatment with an SSRI but not SNRI enhanced motivated foraging behaviour but led to a general impairment in Effort for Reward task output. Together, these data demonstrate that SSRI treatment induces opposing effects on conditioned versus innate motivation which may have significant translational relevance when interpreting drug effect. Further, these behavioural effects differ depending on whether antidepressants are acutely or chronically administered.</p>","PeriodicalId":520722,"journal":{"name":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}