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Ventral Hippocampal Input to Infralimbic Cortex Is Necessary for the Therapeutic-Like Effects of Extinction in Stressed Rats. 海马下部对边缘皮层的输入是应激大鼠消退治疗效应的必要条件
IF 4.5 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-29 DOI: 10.1093/ijnp/pyad043
Denisse Paredes, David A Morilak

Background: Posttraumatic stress disorder is characterized by deficits in cognitive flexibility related to dysfunction of the medial prefrontal cortex (mPFC). Exposure therapy can effectively reverse these deficits. Fear extinction in rodents bears similarity to exposure therapy. Extinction reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST), an mPFC-mediated process. This therapeutic effect requires activity of pyramidal neurons and brain derived neurotrophic factor (BDNF) signaling in infralimbic cortex (IL). However, the circuit mechanisms governing BDNF-mediated plasticity initiated by extinction in IL are unknown. The ventral hippocampus (vHipp) plays a role in regulating IL activity during extinction, and plasticity in vHipp is necessary for extinction memory consolidation. Therefore, we investigated the role of vHipp input to IL in the effects of extinction in reversing stress-induced cognitive deficits.

Methods: vHipp input to IL was silenced using a Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. A day later, rats were tested on AST. In a separate experiment, we tested whether vHipp input to the IL induces BDNF signaling to exert therapeutic effects. We activated the vHipp using a Gq-DREADD, and injected an anti-BDNF neutralizing antibody into IL. Rats were tested on the AST 24 hours later.

Results: Silencing the vHipp input to IL prevented the beneficial effects of extinction in reversing stress-induced cognitive deficits. Activating vHipp input to IL in the absence of extinction was sufficient to reverse stress-induced deficits in set-shifting. The beneficial effects were blocked by local infusion of a neutralizing anti-BDNF antibody into IL.

Conclusions: vHipp-driven BDNF signaling in IL is critical for extinction to counteract the deleterious cognitive effects of chronic stress.

背景:创伤后应激障碍的特点是与内侧前额叶皮层(mPFC)功能障碍有关的认知灵活性缺陷。暴露疗法能有效逆转这些缺陷。啮齿动物的恐惧消退与暴露疗法有相似之处。在由内侧前额叶皮质介导的注意力集合转移测试(AST)中,消退能逆转慢性压力引起的认知灵活性缺陷。这种治疗效果需要锥体神经元的活动和下边缘皮层(IL)的脑源性神经营养因子(BDNF)信号传导。然而,BDNF介导的可塑性在下边缘皮层中由消退启动,其回路机制尚不清楚。腹侧海马(vHipp)在消退过程中起着调节下边缘皮层活动的作用,而vHipp的可塑性是消退记忆巩固的必要条件。因此,我们研究了vHipp对IL的输入在逆转应激诱导的认知缺陷中的作用。方法:在消退前,通过向IL局部注入氯氮平-氧化物(CNO),使用Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD)抑制vHipp对IL的输入。一天后,对大鼠进行 AST 测试。在另一项实验中,我们测试了 vHipp 输入 IL 是否会诱导 BDNF 信号以产生治疗效果。我们使用 Gq-DREADD 激活了 vHipp,并向 IL 注射了抗 BDNF 中和抗体。24小时后对大鼠进行AST测试:结果:抑制vHipp对IL的输入会阻止消退对逆转应激诱导的认知缺陷的有益影响。在没有消减的情况下激活vHipp输入到IL足以逆转应激诱导的集合转移缺陷。结论:vHipp驱动的BDNF信号在IL中对于消退抵消慢性应激的有害认知效应至关重要。
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引用次数: 0
Event-Related Potential Markers of Suicidality in Adolescents. 青少年自杀事件相关的潜在标记。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-29 DOI: 10.1093/ijnp/pyad039
Deniz Doruk Camsari, Charles P Lewis, Ayse Irem Sonmez, Can Ozger, Parmis Fatih, Deniz Yuruk, Julia Shekunov, Jennifer L Vande Voort, Paul E Croarkin

Background: Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates associated with the Death/Suicide Implicit Association Test (DS-IAT) via event-related potentials (ERP) in suicidal adolescents.

Methods: Thirty inpatient adolescents with suicidal ideations and behaviors (SIBS) and 30 healthy controls from the community were recruited. All participants underwent 64-channel electroencephalography, DS-IAT, and clinical assessments. Hierarchical generalized linear models with spatiotemporal clustering were used to identify significant ERPs associated with the behavioral outcome of DS-IAT (D scores) and group differences.

Results: Behavioral results (D scores) showed that the adolescents with SIBS had stronger implicit associations between "death" and "self" than the healthy group (P = .02). Within adolescents with SIBS, participants with stronger implicit associations between "death" and "self" reported more difficulty in controllability of suicidal ideation in the past 2 weeks based on the Columbia-Suicide Severity Rating Scale (P = .03). For the ERP data, the D scores and N100 component over the left parieto-occipital cortex had significant correlations. Significant group differences without behavioral correlation were observed for a second N100 cluster (P = .01), P200 (P = .02), and late positive potential (5 clusters, all P ≤ .02). Exploratory predictive models combining both neurophysiological and clinical measures distinguished adolescents with SIBS from healthy adolescents.

Conclusions: Our results suggest that N100 may be a marker of attentional resources involved in the distinction of stimuli that are congruent or incongruent to associations between death and self. Combined clinical and ERP measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.

背景:内隐认知标记可能有助于预测超出临床危险因素的自杀行为。本研究的目的是通过事件相关电位(ERP)探讨自杀青少年死亡/自杀内隐联想测验(DS-IAT)的神经相关。方法:从社区招募30名有自杀意念和行为(SIBS)的住院青少年和30名健康对照。所有参与者都进行了64通道脑电图、DS-IAT和临床评估。采用具有时空聚类的层次广义线性模型来识别与DS-IAT行为结果(D分数)和组差异相关的显著erp。结果:行为学结果(D分)显示,SIBS青少年的“死亡”与“自我”的内隐关联明显强于健康组(P = .02)。在SIBS青少年中,根据哥伦比亚自杀严重程度评定量表,“死亡”和“自我”之间的内隐关联越强的参与者报告在过去2周内自杀意念的可控制性越困难(P = .03)。对于ERP数据,左侧顶枕皮层的D评分和N100分量具有显著相关性。第二组N100 (P = 0.01)、P200 (P = 0.02)和晚期阳性电位(5组,均P≤0.02)组间差异显著,但无行为相关性。结合神经生理学和临床测量的探索性预测模型将SIBS青少年与健康青少年区分开来。结论:我们的研究结果表明,N100可能是一个注意资源的标记,参与区分与死亡和自我相关的刺激是一致的还是不一致的。结合临床和ERP测量可能在未来改进青少年自杀的评估和治疗方法中有实用价值。
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引用次数: 0
Differential Impacts of Endogenous Antioxidants on Clinical Symptoms and Cognitive Function in Acute and Chronic Schizophrenia Patients. 内源性抗氧化剂对急慢性精神分裂症患者临床症状和认知功能的差异影响
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-29 DOI: 10.1093/ijnp/pyad040
Chieh-Hsin Lin, Tin-May Li, Yu-Jhen Huang, Shaw-Ji Chen, Hsien-Yuan Lane

Background: Impaired antioxidant defense is implicated in the pathophysiology of schizophrenia, and superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) are 3 first-line endogenous antioxidants. Various cognitive functions decline differently during the schizophrenia course. The characteristic roles of the 3 antioxidants in clinical and cognitive profiles in acute and chronic phases of schizophrenia require study.

Methods: We recruited 311 patients with schizophrenia, including 92 acutely exacerbated patients who had been off antipsychotics for at least 2 weeks and 219 chronic patients who had been stable on medication for at least 2 months. Blood SOD, CAT, and GSH levels; clinical symptoms; and 9 cognitive test scores were measured.

Results: Blood CAT levels were higher in the acute patients than in the chronic patients, whereas SOD and GSH levels were similar to one another. Higher CAT levels were correlated with less positive symptoms, better working memory and problem solving in the acute phase, and less negative symptoms, less general psychopathology, better global assessment of function, and better cognitive function (in speed of processing, attention, problem solving) in the chronic period. Higher SOD levels were correlated with better global assessment of function in the acute phase and better speed of processing, working memory, and verbal learning and memory in the chronic period. GSH influenced neither clinical nor cognitive manifestations.

Conclusions: This study showed that blood CAT affected different clinical and cognitive domains between acute and chronic stages of schizophrenia, SOD influenced cognitive functions in chronic state, but GSH affected none. Further studies are needed to explore the underlying mechanisms.

背景:抗氧化防御功能受损与精神分裂症的病理生理有关,超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽(GSH)是3种一线内源性抗氧化剂。在精神分裂症病程中,各种认知功能的下降是不同的。这3种抗氧化剂在精神分裂症急性期和慢性期的临床和认知方面的特征性作用有待研究。方法:我们招募了311例精神分裂症患者,其中92例急性加重患者停用抗精神病药物至少2周,219例慢性患者停用抗精神病药物至少2个月。血SOD、CAT、GSH水平;临床症状;并测量了9项认知测试分数。结果:急性组血CAT水平高于慢性组,SOD和GSH水平相近。较高的CAT水平与急性期较少的阳性症状、较好的工作记忆和问题解决能力相关,与慢性期较少的阴性症状、较低的一般精神病理、较好的整体功能评估和较好的认知功能(处理速度、注意力、问题解决能力)相关。较高的SOD水平与急性期更好的整体功能评估和慢性期更好的加工速度、工作记忆、言语学习和记忆相关。谷胱甘肽对临床和认知表现均无影响。结论:本研究显示血CAT对精神分裂症急性和慢性阶段不同临床和认知领域有影响,SOD对慢性状态的认知功能有影响,而GSH无影响。需要进一步的研究来探索潜在的机制。
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引用次数: 0
Reelin Plasma Levels Identify Cognitive Decline in Alcohol Use Disorder Patients During Early Abstinence: The Influence of APOE4 Expression. Reelin血浆水平识别早期戒酒期间酒精使用障碍患者的认知能力下降:APOE4表达的影响
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-08-29 DOI: 10.1093/ijnp/pyad034
Berta Escudero, Marta Moya, Leticia López-Valencia, Francisco Arias, Laura Orio

Background: Apolipoprotein E (APOE)-4 isoform, reelin, and clusterin share very-low-density liporeceptor and apolipoprotein E receptor 2 receptors and are related to cognition in neuropsychiatric disorders. These proteins are expressed in plasma and brain, but studies involving plasma expression and cognition are scarce.

Methods: We studied the peripheral expression (plasma and peripheral blood mononuclear cells) of these proteins in 24 middle-aged patients with alcohol use disorder (AUD) diagnosed at 4 to 12 weeks of abstinence (t = 0) and 34 controls. Cognition was assessed using the Test of Detection of Cognitive Impairment in Alcoholism. In a follow-up study (t = 1), we measured reelin levels and evaluated cognitive improvement at 6 months of abstinence.

Results: APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively, reaching similar plasma levels in ε4 carriers regardless of whether they were patients with AUD or controls. Plasma reelin and clusterin were higher in the AUD group, and reelin levels peaked in patients expressing APOE4 (P < .05, η2 = 0.09), who showed reduced very-low-density liporeceptor and apolipoprotein E receptor 2 expression in peripheral blood mononuclear cells. APOE4 had a negative effect on memory/learning mainly in the AUD group (P < .01, η2 = 0.15). Multivariate logistic regression analyses identified plasma reelin as a good indicator of AUD cognitive impairment at t = 0. At t = 1, patients with AUD showed lower reelin levels vs controls along with some cognitive improvement.

Conclusions: Reelin plasma levels are elevated during early abstinence in patients with AUD who express the APOE4 isoform, identifying cognitive deterioration to a great extent, and it may participate as a homeostatic signal for cognitive recovery in the long term.

背景:载脂蛋白E (APOE)-4异构体、reelin和clusterin共享极低密度脂蛋白受体和载脂蛋白E受体2受体,并与神经精神疾病的认知有关。这些蛋白在血浆和大脑中表达,但涉及血浆表达和认知的研究很少。方法:我们研究了24例戒酒4 ~ 12周诊断为酒精使用障碍(AUD)的中年患者(t = 0)和34例对照组中这些蛋白的外周表达(血浆和外周血单个核细胞)。使用酒精中毒认知障碍检测测试评估认知能力。在一项随访研究中(t = 1),我们测量了戒断6个月后的reelin水平并评估了认知改善。结果:APOE4亚型分别在37.5%和58.8%的患者和对照组中存在,无论在AUD患者还是对照组中,ε4携带者的血浆水平相似。AUD组血浆reelin和clusterin较高,且reelin水平在APOE4表达的患者中达到峰值(P结论:在APOE4亚型表达的AUD患者中,reelin血浆水平在早期戒断期间升高,在很大程度上识别认知衰退,并可能作为长期认知恢复的稳态信号参与。
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引用次数: 0
Serotonergic Neurotransmission in Limbic Regions May Reflect Therapeutic Response of Depressive Patients: A PET Study With 11C-WAY-100635 and 18F-MPPF. 边缘区5 -羟色胺能神经传递可能反映抑郁症患者的治疗反应:11C-WAY-100635和18F-MPPF的PET研究
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad026
Soichiro Kitamura, Yasuyuki Kimura, Keisuke Takahata, Sho Moriguchi, Manabu Kubota, Hitoshi Shimada, Hironobu Endo, Yuhei Takado, Kazunori Kawamura, Ming-Rong Zhang, Tetsuya Suhara, Makoto Higuchi

Background: Central serotonin (5-hydroxytryptamine [5-HT]) neurotransmission has been implicated in the etiology of depression. Most antidepressants ameliorate depressive symptoms by increasing 5-HT at synaptic clefts, but their effect on 5-HT receptors has yet to be clarified. 11C-WAY-100635 and 18F-MPPF are positron emission tomography (PET) radioligands for 5-HT1A receptors. While binding of both ligands reflects 5-HT1A receptor density, 18F-MPPF biding may also be affected by extracellular 5-HT concentrations. This dual-tracer PET study explored the neurochemical substrates underlying antidepressant effects in patients with depression.

Methods: Eleven patients with depression, including 9 treated with antidepressants, and 16 age- and sex-matched healthy individuals underwent PET scans with 11C-WAY-100635 and 18F-MPPF. Radioligand binding was determined by calculating the nondisplaceable binding potential (BPND).

Results: Patients treated with antidepressants showed significantly lower 18F-MPPF BPND in neocortical regions and raphe nuclei, but not in limbic regions, than controls. No significant group differences in 11C-WAY-100635 BPND were found in any of the regions. Significant correlations of BPND between 11C-WAY-100635 and 18F-MPPF were observed in limbic regions and raphe nuclei of healthy controls, but no such associations were found in antidepressant-treated patients. Moreover, 18F-MPPF BPND in limbic regions was significantly correlated with the severity of depressive symptoms.

Conclusions: These results suggest a diversity of antidepressant-induced extracellular 5-HT elevations in the limbic system among depressive patients, which is associated with the individual variability of clinical symptoms following the treatment.

背景:中枢5-羟色胺(5-羟色胺[5-HT])神经传递与抑郁症的病因有关。大多数抗抑郁药通过增加突触间隙的5-羟色胺来改善抑郁症状,但它们对5-羟色胺受体的作用尚未明确。11C-WAY-100635和18F-MPPF是5-HT1A受体的正电子发射断层扫描(PET)放射配体。虽然这两种配体的结合反映了5-HT1A受体的密度,但18F-MPPF的结合也可能受到细胞外5-HT浓度的影响。这项双示踪PET研究探讨了抑郁症患者抗抑郁作用的神经化学基础。方法:11名抑郁症患者,包括9名接受抗抑郁药物治疗的患者,以及16名年龄和性别匹配的健康个体,使用11C-WAY-100635和18F-MPPF进行PET扫描。通过计算不可置换结合势(BPND)来确定放射性配体的结合。结果:与对照组相比,接受抗抑郁药物治疗的患者新皮质区和中缝核的18F-MPPF BPND显著降低,但边缘区无显著降低。11C-WAY-100635 BPND在所有地区均无显著组间差异。11C-WAY-100635与18F-MPPF在健康对照的边缘区和中缝核中存在显著相关性,但在抗抑郁治疗的患者中未发现这种相关性。此外,边缘区18F-MPPF BPND与抑郁症状的严重程度显著相关。结论:这些结果表明,抑郁患者边缘系统中抗抑郁药诱导的细胞外5-HT升高存在多样性,这与治疗后临床症状的个体差异有关。
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引用次数: 0
New Insights into the Roles of p53 in Central Nervous System Diseases. 关于p53在中枢神经系统疾病中的作用的新见解。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad030
Haili Li, Ze Zhang, Huixin Li, Xinyu Pan, Yue Wang

The transcription factor p53, a widely accepted tumor suppressor, regulates the expression of many oncogenes and their downstream signaling pathways, resulting in a series of biological outcomes. Mutations and deletions of the p53 gene often occur in tumor tissues and are involved in their development. In addition to its role in tumors, p53 has a widespread expression in the brain and participates in most cell processes, such as dendrite formation, oxidative stress, apoptosis, autophagy, DNA repair, and cell cycle arrest. Therefore, abnormalities in p53 and its related signaling pathways play an important role in the diagnosis and treatment of central nervous system diseases. This review mainly discusses the latest findings regarding the role of p53 in some central nervous system diseases, such as brain tumors, Alzheimer disease, Parkinson disease, autism, epilepsy, spinocerebellar ataxia, and so on, to provide a comprehensive interpretation of the treatment of neurological diseases from a new perspective.

转录因子p53是一种被广泛接受的肿瘤抑制因子,它调节许多癌基因及其下游信号通路的表达,导致一系列生物学结果。p53基因的突变和缺失经常发生在肿瘤组织中,并参与其发展。除了在肿瘤中发挥作用外,p53在大脑中广泛表达,并参与大多数细胞过程,如树突形成、氧化应激、细胞凋亡、自噬、DNA修复和细胞周期阻滞。因此,p53及其相关信号通路的异常在中枢神经系统疾病的诊断和治疗中具有重要作用。本文主要综述了p53在脑肿瘤、阿尔茨海默病、帕金森病、自闭症、癫痫、脊髓小脑共济失调等中枢神经系统疾病中作用的最新发现,以期从新的角度对神经系统疾病的治疗提供全面的解释。
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引用次数: 1
Nociceptin Receptor Antagonism Modulates Electrophysiological Markers of Reward Learning. 痛觉肽受体拮抗调节报偿学习的电生理标记。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad031
Ann M Iturra-Mena, Brian D Kangas, Diego A Pizzagalli
Using in vivo electrophysiology and a reward-learning task reverse-translated from humans, this study tested the hypothesis that a nociceptin (NOP) receptor antagonist (J-113397) would potentiate behavioral and electrophysiological markers of reward learning in rats. Relative to vehicle, the NOP antagonist modulated electrophysiological markers of reward processing but did not affect response bias toward a more frequently rewarded stimulus. This proof-of-concept study provides initial insights into the effects of NOP receptor antagonism on reward learning, which are consistent with previous findings suggesting that such mechanism is a promising antidepressant target.
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引用次数: 1
Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis. 奥氮平治疗首发精神病或早期精神分裂症患者体重增加和代谢变化:一项荟萃分析
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad029
Christoph U Correll, Mikkel Højlund, Christine Graham, Mark S Todtenkopf, David McDonnell, Adam Simmons

Background: Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population.

Methods: PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5.

Results: Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration.

Conclusions: In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

背景:首发精神病或早期精神分裂症患者易发生与奥氮平相关的体重增加和心脏代谢失调。本荟萃分析描述了随机临床试验中奥氮平治疗期间观察到的体重和代谢影响。方法:检索PubMed、EMBASE和Dialog中报告体重或心脏代谢结果与奥氮平治疗首发精神病或早期精神分裂症相关的随机对照试验(rct)。随机效应meta分析和meta回归采用R v4.0.5进行。结果:在确定的1203份记录中,26项随机对照试验为分析提供了信息。在接受奥氮平治疗体重增加的研究(n = 19)中,meta分析的平均(95% CI)体重增加为7.53 (6.42-8.63)kg。按持续时间分层,持续时间>13周的研究的平均体重增加(95% CI)显著高于持续时间≤13周的研究:分别为11.35(10.05-12.65)和5.51 (4.73-6.28)kg。尽管研究之间存在差异,但在≤13周和>13周的研究中,大多数血糖和脂质参数较基线的增加通常很小。然而,当按研究持续时间分层时,体重增加与代谢参数变化之间没有相关性。结论:在纳入首发精神病或早期精神分裂症患者的随机对照试验中,奥氮平与体重增加一致相关,在持续>13周的研究中体重增加大于≤13周的研究。研究中观察到的代谢变化表明,随机对照试验可能低估了代谢后遗症与实际治疗观察结果。首发精神病或早期精神分裂症患者易患奥氮平相关体重增加;应该仔细考虑最小化奥氮平相关体重增加的策略。
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引用次数: 0
BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice. BTRX-246040通过小鼠腹外侧导水管周围灰质发挥抗抑郁相关作用。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad027
Zhenlong Li, Yuanyuan Xu, Rourou Li, Zhenyu Sheng, Xinya Chen, Xueman Liu, Chau-Shoun Lee, Hsien-Yu Peng, Tzer-Bin Lin, Ming-Chun Hsieh, Cheng-Yuan Lai, Han-Fang Wu, Dylan Chou

Background: BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).

Methods: The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.

Results: Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.

Conclusions: The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.

背景:BTRX-246040是一种痛感肽/孤啡肽FQ受体拮抗剂,正在开发用于治疗抑郁症患者。然而,这种潜在抗抑郁药的潜在机制仍不清楚。在此,我们研究了BTRX-246040在腹外侧导水管周围灰质(vlPAG)中的抗抑郁相关作用。方法:采用悬尾试验、强迫游泳试验、雌性嗅尿试验、蔗糖偏好试验、习得性无助(LH)试验等方法,结合药理学方法,观察h诱导C57BL/6J小鼠抑郁样行为的抗抑郁作用和药物作用。利用电生理记录研究vlPAG神经元的突触活动。结果:BTRX-246040腹腔注射具有剂量依赖性的抗抑郁样行为效应。全身BTRX-246040 (10 mg/kg)导致vlPAG中微型兴奋性突触后电流(EPSCs)的频率和幅度增加。此外,切片灌注BTRX-246040可直接提高微型EPSCs的频率和振幅,并增强被痛感肽/孤儿肽受体激动剂Ro 64-6198预处理的vlPAG中诱发的EPSCs。此外,在vlpag内应用BTRX-246040产生了剂量依赖的抗抑郁样行为效应。此外,6-氰基-7-硝基喹啉-2,3-二酮在vlpag内预处理可逆转全身和局部btrx -246040介导的抗抑郁样行为效应。此外,全身和局部BTRX-246040均可降低LH表型,并减少LH诱导的抑郁样行为。结论:BTRX-246040可能通过vlPAG发挥抗抑郁相关作用。本研究为BTRX-246040抗抑郁样作用的vlpag依赖机制提供了新的见解。
{"title":"BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice.","authors":"Zhenlong Li,&nbsp;Yuanyuan Xu,&nbsp;Rourou Li,&nbsp;Zhenyu Sheng,&nbsp;Xinya Chen,&nbsp;Xueman Liu,&nbsp;Chau-Shoun Lee,&nbsp;Hsien-Yu Peng,&nbsp;Tzer-Bin Lin,&nbsp;Ming-Chun Hsieh,&nbsp;Cheng-Yuan Lai,&nbsp;Han-Fang Wu,&nbsp;Dylan Chou","doi":"10.1093/ijnp/pyad027","DOIUrl":"https://doi.org/10.1093/ijnp/pyad027","url":null,"abstract":"<p><strong>Background: </strong>BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG).</p><p><strong>Methods: </strong>The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity.</p><p><strong>Results: </strong>Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior.</p><p><strong>Conclusions: </strong>The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"26 7","pages":"483-495"},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fc/4f/pyad027.PMC10388391.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10300244","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: 1
A Stress Protein-Based Suicide Prediction Score and Relationship to Reported Early-Life Adversity and Recent Life Stress. 基于应激蛋白的自杀预测评分及其与早期生活逆境和近期生活压力的关系。
IF 4.8 2区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2023-07-31 DOI: 10.1093/ijnp/pyad025
Mark D Underwood, Hanga Galfalvy, Shu-Chi Hsiung, Yan Liu, Norman R Simpson, Mihran J Bakalian, Gorazd B Rosoklija, Andrew J Dwork, Victoria Arango, J John Mann

Background: The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24).

Methods: Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots.

Results: There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated "suicide risk score" using these measures had 71% sensitivity and 71% specificity.

Conclusion: A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.

背景:下丘脑-垂体-肾上腺(HPA)轴是一个主要的应激反应系统,过度的HPA反应可影响重度抑郁症和自杀。我们研究了死后人类前额叶皮层(BA9)和前扣带皮层(BA24)中报告的早期生活逆境(ELA)、近期生活压力(RLS)、自杀与促肾上腺皮质激素释放激素(CRH)、CRH结合蛋白、fk506结合蛋白(FKBP5)、糖皮质激素受体(GR)和脑源性神经营养因子(BDNF)之间的关系。方法:选取性别、年龄、死亡时间相匹配的自杀者和健康对照者共13对四胞胎,分为有ELA组和无ELA组。ELA、RLS和精神病学诊断通过心理解剖确定。western blots检测蛋白水平。结果:BA9、BA24中CRH、CRH结合蛋白、GR、FKBP5与ELA无相关性,自杀与ELA无交互作用(P > 0.05)。对于BDNF, BA24中自杀与ELA存在交互作用;没有ELA的自杀者的BDNF低于没有ELA的对照组,ELA对照组的BDNF低于没有ELA的对照组。前扣带皮层BA9的CRH和FKBP5与RLS呈负相关。最小绝对收缩和选择算子logistic回归交叉验证发现,BDNF、GR和FKBP5 BA24水平联合预测自杀,但ELA没有贡献。使用这些方法计算出的“自杀风险评分”有71%的敏感性和71%的特异性。结论:下丘脑轴异常与自杀有关,与ELA无关。RLS与特定脑区HPA轴蛋白的选择有关。BDNF似乎在ELA和自杀中以特定区域的方式失调。
{"title":"A Stress Protein-Based Suicide Prediction Score and Relationship to Reported Early-Life Adversity and Recent Life Stress.","authors":"Mark D Underwood,&nbsp;Hanga Galfalvy,&nbsp;Shu-Chi Hsiung,&nbsp;Yan Liu,&nbsp;Norman R Simpson,&nbsp;Mihran J Bakalian,&nbsp;Gorazd B Rosoklija,&nbsp;Andrew J Dwork,&nbsp;Victoria Arango,&nbsp;J John Mann","doi":"10.1093/ijnp/pyad025","DOIUrl":"https://doi.org/10.1093/ijnp/pyad025","url":null,"abstract":"<p><strong>Background: </strong>The hypothalamic-pituitary-adrenal (HPA) axis is a major stress response system, and excessive HPA responses can impact major depressive disorder and suicide. We examined relationships between reported early-life adversity (ELA), recent-life stress (RLS), suicide, and corticotropin-releasing hormone (CRH), CRH binding protein, FK506-binding protein (FKBP5), glucocorticoid receptor (GR), and brain-derived neurotrophic factor (BDNF) in postmortem human prefrontal cortex (BA9), and anterior cingulate cortex (BA24).</p><p><strong>Methods: </strong>Thirteen quadruplets, matched for sex, age, and postmortem interval and consisting of suicide decedents and healthy controls, were divided equally into those with and without ELA. ELA, RLS, and psychiatric diagnoses were determined by psychological autopsy. Protein levels were determined by western blots.</p><p><strong>Results: </strong>There were no suicide- or ELA-related differences in CRH, CRH binding protein, GR, or FKBP5 in BA9 or BA24 and no interaction between suicide and ELA (P > .05). For BDNF, there was an interaction between suicide and ELA in BA24; suicides without ELA had less BDNF than controls without ELA, and controls with ELA had less BDNF than controls without ELA. CRH in BA9 and FKBP5 in anterior cingulate cortex correlated negatively with RLS. Least Absolute Shrinkage and Selection Operator logistic regression with cross-validation found combining BDNF, GR, and FKBP5 BA24 levels predicted suicide, but ELA did not contribute. A calculated \"suicide risk score\" using these measures had 71% sensitivity and 71% specificity.</p><p><strong>Conclusion: </strong>A dysregulated HPA axis is related to suicide but not with ELA. RLS was related to select HPA axis proteins in specific brain regions. BDNF appears to be dysregulated in a region-specific way with ELA and suicide.</p>","PeriodicalId":14134,"journal":{"name":"International Journal of Neuropsychopharmacology","volume":"26 7","pages":"501-512"},"PeriodicalIF":4.8,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/47/pyad025.PMC10388383.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9934612","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: 1
期刊
International Journal of Neuropsychopharmacology
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