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Ketone Supplementation Dampens Subjective and Objective Responses to Alcohol: Evidence From a Preclinical Rat Study and a Randomized, Cross-Over Trial in Healthy Volunteers. 补充酮可抑制对酒精的主观和客观反应:来自临床前大鼠研究和健康志愿者随机交叉试验的证据。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-01 DOI: 10.1093/ijnp/pyae009
Xinyi Li, Zhenhao Shi, Dustin R Todaro, Timothy Pond, Juliana I Byanyima, Sianneh A Vesslee, Rishika Reddy, Ravi Prakash Reddy Nanga, Gabriel Kass, Vijay Ramchandani, Henry R Kranzler, Janaina C M Vendruscolo, Leandro F Vendruscolo, Corinde E Wiers

Background: Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown.

Methods: In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-β-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure.

Results: In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water.

Conclusion: KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol.

背景:以往的临床前研究和人体研究表明,高脂生酮饮食和酮补充剂(KS)可有效减少酒精渴求、酒精消耗和酒精戒断症状。然而,生酮饮食对酒精敏感性的影响尚不清楚:在这项单盲、交叉研究中,10 名健康参与者(3 名女性)在口服酒精剂量(女性为 0.25 克/千克;男性为 0.31 克/千克)前 30 分钟口服单剂量 KS(25 克来自 D-β-羟丁酸和 R-1,3-丁二醇的酮)或安慰剂。在饮酒后 180 分钟内,反复进行呼气酒精浓度(BrAC)和血液酒精浓度(BAL)评估以及药物效应问卷调查。在一项平行的临床前研究中,8 只 Wistar 大鼠(4 只雌性)先口服 KS(0.42 克酮/千克)、水或甜味剂阿尿糖(0.58 克/千克),15 分钟后再口服酒精剂量(0.8 克/千克)。在接触酒精 240 分钟后监测 BAL:结果:在人类中,饮酒前摄入 KS 会明显减弱 BrAC 和 BAL,降低对喜欢和想要更多酮/酒精的评价,并增加对所感受到的影响的反感。在大鼠身上,KS 比阿尿糖或水更能降低 BAL:结论:KS 改变了人类和大鼠对酒精的生理和主观反应,其影响很可能不是由 KS 饮料中的甜味剂阿洛糖介导的。因此,KS 有可能降低酒精的醉酒效应。
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引用次数: 0
PI3K-AKT/mTOR Signaling in Psychiatric Disorders: A Valuable Target to Stimulate or Suppress? 精神疾病中的 PI3K-AKT/mTOR 信号:是刺激还是抑制的重要目标?
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-01 DOI: 10.1093/ijnp/pyae010
Yan Chen, Wei Guan, Mei-Lan Wang, Xiao-Yun Lin

Economic development and increased stress have considerably increased the prevalence of psychiatric disorders in recent years, which rank as some of the most prevalent diseases globally. Several factors, including chronic social stress, genetic inheritance, and autogenous diseases, lead to the development and progression of psychiatric disorders. Clinical treatments for psychiatric disorders include psychotherapy, chemotherapy, and electric shock therapy. Although various achievements have been made researching psychiatric disorders, the pathogenesis of these diseases has not been fully understood yet, and serious adverse effects and resistance to antipsychotics are major obstacles to treating patients with psychiatric disorders. Recent studies have shown that the mammalian target of rapamycin (mTOR) is a central signaling hub that functions in nerve growth, synapse formation, and plasticity. The PI3K-AKT/mTOR pathway is a critical target for mediating the rapid antidepressant effects of these pharmacological agents in clinical and preclinical research. Abnormal PI3K-AKT/mTOR signaling is closely associated with the pathogenesis of several neurodevelopmental disorders. In this review, we focused on the role of mTOR signaling and the related aberrant neurogenesis in psychiatric disorders. Elucidating the neurobiology of the PI3K-AKT/mTOR signaling pathway in psychiatric disorders and its actions in response to antidepressants will help us better understand brain development and quickly identify new therapeutic targets for the treatment of these mental illnesses.

近年来,经济的发展和压力的增加大大提高了精神疾病的发病率,使其成为全球最普遍的疾病之一。慢性社会压力、遗传和自身疾病等多种因素导致了精神障碍的发生和发展。精神障碍的临床治疗方法包括心理治疗、化学治疗和电击治疗。虽然对精神疾病的研究取得了各种成果,但这些疾病的发病机理尚未完全清楚,严重的副作用和对抗抑郁药物的耐药性是治疗精神疾病患者的主要障碍。最近的研究表明,哺乳动物雷帕霉素靶标(mTOR)是神经生长、突触形成和可塑性的核心信号枢纽。在临床和临床前研究中,PI3K-AKT/mTOR 通路是介导这些药理制剂快速抗抑郁作用的关键靶点。PI3K-AKT/mTOR信号异常与多种神经发育障碍的发病机制密切相关。在这篇综述中,我们重点探讨了 mTOR 信号的作用以及与之相关的神经发生异常在精神疾病中的作用。阐明 PI3K-AKT/mTOR 信号通路在精神疾病中的神经生物学作用及其对抗抑郁药的作用,将有助于我们更好地理解大脑发育,并迅速确定治疗这些精神疾病的新靶点。
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引用次数: 0
A Systematic Review of the Molecular and Cellular Alterations Induced by Cannabis That May Serve as Risk Factors for Bipolar Disorder. 大麻诱发的分子和细胞变化可能成为躁郁症风险因素的系统回顾。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-01 DOI: 10.1093/ijnp/pyae002
Alejandra Delgado-Sequera, Clara Garcia-Mompo, Ana Gonzalez-Pinto, Maria Hidalgo-Figueroa, Esther Berrocoso

Background: Cannabis use is a risk factor of psychiatric illness, such as bipolar disorder type-I (BDI). Indeed, cannabis use strongly influences the onset and clinical course of BDI, although the biological mechanisms underlying this interaction remain unknown. Therefore, we have reviewed the biological mechanisms affected by cannabis use that may trigger BD.

Methods: A systematic review was carried out of articles in which gene expression was studied in cannabis users or human-derived cells exposed to tetrahydrocannabinol (THC) or cannabidiol (CBD). A second systematic review was then performed to identify articles in which gene expression was studied in BDI samples, highlighting those that described alterations to the same molecular and cellular mechanisms affected by cannabis/THC/CBD.

Results: The initial search identified 82 studies on cannabis and 962 on BDI. After removing duplicates and applying the inclusion/exclusion criteria, 9 studies into cannabis and 228 on BDI were retained. The molecular and cellular mechanisms altered by cannabis use or THC/CBD exposure were then identified, including neural development and function, cytoskeletal function, cell adhesion, mitochondrial biology, inflammatory related pathways, lipid metabolism, the endocannabinoid system, the hypocretin/orexin system, and apoptosis. Alterations to those activities were also described in 19 of 228 focused on BDI.

Conclusions: The biological mechanisms described in this study may be good candidates to the search for diagnostic biomarkers and therapeutic targets for BDI. Because cannabis use can trigger the onset of BD, further studies would be of interest to determine whether they are involved in the early development of the disorder, prompting early treatment.

背景:吸食大麻是罹患躁郁症(BDI)等精神疾病的风险因素之一。事实上,吸食大麻对躁狂症的发病和临床过程有很大影响,但这种相互作用的生物机制仍不清楚。因此,我们回顾了受大麻使用影响而可能引发躁郁症的生物机制:方法:我们对研究大麻使用者或暴露于四氢大麻酚或 CBD 的人源细胞基因表达的文章进行了系统综述。然后进行了第二次系统综述,以确定对 BDI 样本中基因表达进行研究的文章,重点是那些描述了受大麻/四氢大麻酚/CBD 影响的相同分子和细胞机制变化的文章:初步搜索确定了 82 项关于大麻的研究和 962 项关于 BDI 的研究。在去除重复内容并应用纳入/排除标准后,保留了 9 项关于大麻的研究和 228 项关于 BDI 的研究。然后确定了因吸食大麻或接触四氢大麻酚/CBD 而改变的分子和细胞机制,包括:神经发育和功能、细胞骨架功能、细胞粘附、线粒体生物学、炎症相关途径、脂质代谢、内源性大麻素系统、视网膜下素/视黄醇系统和细胞凋亡。在 228 项关注 BDI 的研究中,有 19 项也描述了这些活动的改变:本研究中描述的生物机制可能是寻找 BDI 诊断生物标志物和治疗目标的良好候选者。由于吸食大麻可诱发 BD 发病,进一步的研究将有助于确定它们是否参与了该疾病的早期发展,从而促进早期治疗。
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引用次数: 0
Evenamide: A Potential Pharmacotherapeutic Alternative for Treatment-Resistant Schizophrenia. 偶氮酰胺:治疗耐药性精神分裂症的潜在药物疗法替代品。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-01 DOI: 10.1093/ijnp/pyae005
Raghunath Singh, Margaret K Hahn, Yashika Bansal, Sri Mahavir Agarwal, Gary Remington
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引用次数: 0
Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia: Results for the 6-Month Formulation From an Open-label Extension Study Compared to Real-World Data for the 1-Month and 3-Month Formulations. 帕潘立酮棕榈酸酯治疗成人精神分裂症患者的复发率:为期 6 个月的开放标签延长期研究结果与为期 1 个月和 3 个月制剂的实际数据对比。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-02-01 DOI: 10.1093/ijnp/pyad067
Ibrahim Turkoz, Mehmet Daskiran, Uzma Siddiqui, R Karl Knight, Karen L Johnston, Christoph U Correll

Background: The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month (PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from an open-label extension (OLE) study in adult patients with schizophrenia.

Methods: PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophrenia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria as the PP6M cohort.

Results: A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%; mean age: 39-41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11 [0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and completeness of clinical information.

Conclusions: In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia.

Trial registration: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.

背景:帕利哌酮棕榈酸酯(PP)的三种长效注射抗精神病药物配方,即PP 1个月(PP1M)、PP 3个月(PP3M)和PP 6个月(PP6M),已被证明可降低精神分裂症的复发风险。目前的第四阶段研究利用PP3M和PP1M的真实世界数据构建了外部比较臂(ECA),并将精神分裂症成人患者的复发预防率与开放标签扩展(OLE)研究中的PP6M进行了比较:PP6M的数据来自一项为期24个月的单臂OLE研究(NCT04072575),该研究纳入了完成了为期12个月的随机、双盲(DB)、非劣效、3期研究(NCT03345342)且未复发的精神分裂症患者。PP3M 和 PP1M ECA 中的患者是从 IBM® MarketScan® 多州医疗补助数据库中根据与 PP6M 队列相似的资格标准确定的:经过倾向得分匹配后,每个队列共纳入了 178 名患者。大多数患者为男性(>70%);平均年龄为 39-41 岁。PP6M队列的复发时间(基于Kaplan-Meier估计值的主要分析)明显推迟(PC结论:在临床试验中,PP6M队列的复发时间比PP6M队列明显推迟:在临床试验中,与PP3M和PP1M治疗相比,PP6M可显著延迟精神分裂症成年患者的复发时间,并降低复发率。
{"title":"Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia: Results for the 6-Month Formulation From an Open-label Extension Study Compared to Real-World Data for the 1-Month and 3-Month Formulations.","authors":"Ibrahim Turkoz, Mehmet Daskiran, Uzma Siddiqui, R Karl Knight, Karen L Johnston, Christoph U Correll","doi":"10.1093/ijnp/pyad067","DOIUrl":"10.1093/ijnp/pyad067","url":null,"abstract":"<p><strong>Background: </strong>The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month (PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from an open-label extension (OLE) study in adult patients with schizophrenia.</p><p><strong>Methods: </strong>PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophrenia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria as the PP6M cohort.</p><p><strong>Results: </strong>A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%; mean age: 39-41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11 [0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and completeness of clinical information.</p><p><strong>Conclusions: </strong>In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10873782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ketamine or ECT? What Have We Learned From the KetECT and ELEKT-D Trials? 氯胺酮还是电痉挛疗法?我们从 KetECT 和 ELEKT-D 试验中学到了什么?
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.1093/ijnp/pyad065
Joakim Ekstrand, Akihiro Takamiya, Axel Nordenskjold, George Kirov, Pascal Sienaert, Charles H Kellner, Pouya Movahed Rad

1. Two recent clinical trials, KetECT and ELEKT-D, compared the effectiveness of ketamine and electroconvulsive therapy (ECT) for major depressive disorder. Notably, these trials reported marked differences in ECT's clinical outcomes of, with remission rates of 63% for KetECT and a strikingly lower rate of 22% for ELEKT-D, while the remission rates for ketamine were 46% and 38%, respectively. Considering that the primary objective of both trials was to compare the standard treatment (ECT) with an experimental intervention (ketamine), it is crucial to highlight the pronounced disparities in ECT's clinical outcomes. This article offers a comprehensive comparison of these trials while also exploring how patient characteristics, treatment protocols, and study designs may contribute to such pronounced outcome discrepancies. These differences highlight the heterogeneous nature of depression and underscore the need for personalized treatments. These studies also provide valuable insights into identifying the most suitable candidates for ketamine and ECT.

最近进行的两项临床试验(KetECT 和 ELEKT-D)比较了氯胺酮和电休克疗法(ECT)对重度抑郁症的疗效。值得注意的是,这些试验报告显示,电休克疗法的临床疗效存在明显差异,KetECT的缓解率为63%,而ELEKT-D的缓解率则低得惊人,仅为22%,而氯胺酮的缓解率分别为46%和38%。考虑到这两项试验的主要目的是比较标准疗法(电痉挛疗法)和实验性干预(氯胺酮),因此强调电痉挛疗法临床疗效的明显差异至关重要。本文对这些试验进行了全面的比较,同时还探讨了患者特征、治疗方案和研究设计是如何导致如此明显的结果差异的。这些差异凸显了抑郁症的异质性,强调了个性化治疗的必要性。这些研究还为确定氯胺酮和电痉挛疗法的最合适人选提供了宝贵的见解。
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引用次数: 0
Corrigendum to: Characterization of 2 Novel Phosphodiesterase 2 Inhibitors Hcyb1 and PF-05180999 on Depression- and Anxiety-Like Behavior. 更正:两种新型磷酸二酯酶2抑制剂Hcyb1和PF-05180999对抑郁和焦虑行为的表征。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.1093/ijnp/pyad068
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引用次数: 0
Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats. 慢性应激诱导的黑色素浓缩荷尔蒙在大鼠神经节位置的升高会抑制去甲肾上腺素的分泌,并与抑郁样行为相关。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.1093/ijnp/pyad069
Nurhumar Kurban, Yu Qin, Hui-Ling Zhao, Xiao Hu, Xi Chen, Yi-Yi Zhao, Yu-Shuo Peng, Hong-Bo Wang, Su-Ying Cui, Yong-He Zhang

Background: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine.

Method: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors.

Results: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine β hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling.

Conclusions: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

背景:黑色素浓缩激素(MCH)是一种下丘脑神经肽,可投射到整个中枢神经系统,包括去甲肾上腺素能区(LC)。我们之前的研究表明,LC 中的 MCH/MCH 受体 1(MCHR1)可能参与了抑郁症的调控。本研究探讨了MCH/MCHR1在抑郁样行为中的作用是否与去甲肾上腺素的调节有关:方法:慢性不可预测应激(CUS)和急性LC内显微注射MCH诱导大鼠抑郁样行为。此外,还在大鼠LC内注射了MCHR1拮抗剂SNAP-94847。行为评估采用了蔗糖偏好、强迫游泳和运动试验。采用免疫荧光染色、ELISA、Western blot和HPLC-ECD等方法探讨MCH/MCHR1在抑郁样行为中的调控机制:结果:CUS诱导LC中MCH水平异常升高并下调MCHR1,这与抑郁样行为的形成高度相关。SNAP-94847通过使LC中的酪氨酸羟化酶、多巴胺β羟化酶和去甲肾上腺素正常化,对暴露于CUS的大鼠产生抗抑郁作用。通过对 MCHR1 的作用,MCH 的急性显微注射可诱导抑郁样行为。在LC中拮抗MCHR1可使MCHR1介导的cAMP-PKA信号转导正常化,从而显著逆转MCH诱导的去甲肾上腺素分泌下调:我们的研究证实,LC 中的 MCH/MCHR1 系统可能通过下调去甲肾上腺素的分泌参与了抑郁样行为。这些结果加深了我们对与 LC 中 MCH/MCHR1 系统有关的抑郁症发病机制的理解。
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引用次数: 0
The Ability to Voluntarily Regulate Theta Band Activity Affects How Pharmacological Manipulation of the Catecholaminergic System Impacts Cognitive Control. 自愿调节θ波段活动的能力会影响对儿茶酚胺能系统的药物治疗对认知控制的影响。
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.1093/ijnp/pyae003
Astrid Prochnow, Moritz Mückschel, Elena Eggert, Jessica Senftleben, Christian Frings, Alexander Münchau, Veit Roessner, Annet Bluschke, Christian Beste

Background: The catecholaminergic system influences response inhibition, but the magnitude of the impact of catecholaminergic manipulation is heterogeneous. Theoretical considerations suggest that the voluntary modulability of theta band activity can explain this variance. The study aimed to investigate to what extent interindividual differences in catecholaminergic effects on response inhibition depend on voluntary theta band activity modulation.

Methods: A total of 67 healthy adults were tested in a randomized, double-blind, cross-over study design. At each appointment, they received a single dose of methylphenidate or placebo and performed a Go/Nogo task with stimuli of varying complexity. Before the first appointment, the individual's ability to modulate theta band activity was measured. Recorded EEG data were analyzed using temporal decomposition and multivariate pattern analysis.

Results: Methylphenidate effects and voluntary modulability of theta band activity showed an interactive effect on the false alarm rates of the different Nogo conditions. The multivariate pattern analysis revealed that methylphenidate effects interacted with voluntary modulability of theta band activity at a stimulus processing level, whereas during response selection methylphenidate effects interacted with the complexity of the Nogo condition.

Conclusions: The findings reveal that the individual's theta band modulability affects the responsiveness of an individual's catecholaminergic system to pharmacological modulation. Thus, the impact of pharmacological manipulation of the catecholaminergic system on cognitive control most likely depends on the existing ability to self-modulate relevant brain oscillatory patterns underlying the cognitive processes being targeted by pharmacological modulations.

背景:儿茶酚胺能系统会影响反应抑制,但儿茶酚胺能操作的影响程度却不尽相同。理论上认为,θ波段活动的自愿可调控性可以解释这种差异。本研究旨在探讨儿茶酚胺能对反应抑制作用的个体间差异在多大程度上取决于θ波段活动的自愿调节:方法:67 名健康成年人接受了随机、双盲、交叉研究设计的测试。在每次预约时,他们都会接受单剂量的哌醋甲酯或安慰剂,并在不同复杂度的刺激下完成 Go/Nogo 任务。在第一次约见之前,对患者调节θ波段活动的能力进行了测量。记录的脑电图数据通过时间分解和多变量模式分析(MVPA)进行了分析:结果:哌醋甲酯效应和θ波段活动的自主可调控性对不同 Nogo 条件下的误报率有交互影响。MVPA显示,哌醋甲酯效应与θ波段活动的自愿可调控性在刺激加工层面上相互作用,而在反应选择过程中,哌醋甲酯效应与Nogo条件的复杂性相互作用:研究结果表明,个体的θ波段可调控性会影响个体儿茶酚胺能系统对药物调控的反应性。因此,对儿茶酚胺能系统的药理调控对认知控制的影响很可能取决于现有的自我调节能力,而自我调节能力又是药理调控所针对的认知过程的基础。
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引用次数: 0
MiR-182-5p: A Novel Biomarker in the Treatment of Depression in CSDS-Induced Mice. MiR-182-5p:一种治疗csds诱导小鼠抑郁的新型生物标志物
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-01-01 DOI: 10.1093/ijnp/pyad064
Ya-Bin Zheng, Xiao-Ming Sheng, Xiang Jin, Wei Guan

Background: Depression is a neuropsychiatric disease with a high disability rate and mainly caused by the chronic stress or genetic factors. There is increasing evidence that microRNAs (miRNAs) play a critical role in the pathogenesis of depression. However, the underlying molecular mechanism for the pathophysiology of depression of miRNA remains entirely unclear so far.

Methods: We first established a chronic social defeat stress (CSDS) mice model of depression, and depression-like behaviors of mice were evaluated by a series of behavioral tests. Next, we detected several abundantly expressive miRNAs suggested in previous reports to be involved in depression and found miR-182-5p was selected as a candidate for analysis in the hippocampus. Then western blotting and immunofluorescence were used together to examine whether adeno-associated virus (AAV)-siR-182-5p treatment alleviated chronic stress-induced decrease in hippocampal Akt/GSK3β/cAMP-response element binding protein (CREB) signaling pathway and increase in neurogenesis impairment and neuroinflammation. Furthermore, CREB inhibitor was adopted to examine if blockade of Akt/GSK3β/CREB signaling pathway abolished the antidepressant actions of AAV-siR-182-5p in mice.

Results: Knockdown of miR-182-5p alleviated depression-like behaviors and impaired neurogenesis of CSDS-induced mice. Intriguingly, the usage of agomiR-182-5p produced significant increases in immobility times and aggravated neuronal neurogenesis damage of mice. More importantly, it suggested that 666-15 blocked the reversal effects of AAV-siR-182-5p on the CSDS-induced depressive-like behaviors in behavioral testing and neuronal neurogenesis within hippocampus of mice.

Conclusions: These findings indicated that hippocampal miR-182-5p/Akt/GSK3β/CREB signaling pathway participated in the pathogenesis of depression, and it might give more opportunities for new drug developments based on the miRNA target in the clinic.

背景:抑郁症是一种致残率高的神经精神疾病,主要由慢性应激或遗传因素引起。越来越多的证据表明,mirna在抑郁症的发病机制中起着至关重要的作用。然而,到目前为止,miRNA抑制病理生理的潜在分子机制仍然完全不清楚。方法:首先建立慢性社会失败应激(CSDS)小鼠抑郁模型,通过一系列行为测试评估小鼠的抑郁样行为。接下来,我们检测了几个在以前的报道中被认为参与抑郁的高表达mirna,并发现miR-182-5p被选为海马的候选分析,然后使用western blotting和免疫荧光一起检测AAV-siR-182-5p治疗是否缓解了慢性应激诱导的海马Akt/GSK3β/CREB信号通路的减少以及神经发生损伤和神经炎症的增加。此外,我们采用camp反应元件结合蛋白(CREB)抑制剂来检测阻断Akt/GSK3β/CREB信号通路是否会消除小鼠AAV-siR-182-5p的抗抑郁作用。结果:miR-182-5p敲低可减轻csds诱导小鼠的抑郁样行为和神经发生受损。有趣的是,agomiR-182-5p的使用显著增加了小鼠的静止时间,加重了神经元神经发生损伤。更重要的是,666-15阻断了AAV-siR-182-5p在行为学测试中对csds诱导的抑郁样行为和海马内神经元神经发生的逆转作用。结论:这些发现提示海马miR-182-5p/Akt/GSK3β/CREB信号通路参与了抑郁症的发病机制,临床中基于miRNA靶点的新药开发可能会有更多的机会。
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International Journal of Neuropsychopharmacology
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