中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 沈旭日, 刘福旺, 侯雪芹
, SHEN Xuri, LIU Fuwang, HOU Xueqin,
缩宫素是一种肽类激素,由垂体后叶分泌,经下丘脑的室旁核和视上核合成。缩宫素具有促进妊娠子宫平滑肌收缩和乳腺肌上皮收缩(排乳)的功能。近年来,缩宫素与脑内缩宫素受体结合产生的生理作用在中枢神经系统疾病领域受到广泛关注。该文回顾并总结缩宫素在中枢神经系统疾病中的研究进展及缩宫素类似物的应用,以期为缩宫素临床应用及新药研究开发提供参考。
Oxytocin (OT) is a peptide hormone secreted by the posterior pituitary gland and synthesized through the paraventricular nucleus and supraoptic nucleus of the hypothalamus.For a long time,it has been known that OT has the function of promoting the contraction of the smooth muscle of the uterus and the contraction of the myoepithelium of the mammary gland (lactation).In addition to the above two classical functions,the physiological effect of OT binding to oxytocin receptors in the brain has attracted wide attention in central nervous system diseases.This paper reviews and summarizes the research progress of OT in central nervous system diseases,and discusses the possible mechanism of OT,in order to provide a theoretical basis for the clinical application of OT and the development of new drugs.
开放科学(资源服务)标识码(OSID)
缩宫素作为多效性的垂体环状神经九肽,包含氨基酸六元环结构和3个单氨基酸[3],主要由哺乳动物下丘脑双侧视上核(supraoptic nucleus,SON)和脑室旁核(paraventricular nucleus,PVN)以及副核等细胞神经元合成,少数散在终纹床核区(bed nucleus of the stria terminalis,BNST)[4]。
焦虑是一种紧张不安的复杂情绪状态,而抑郁则表现为情绪低落、兴趣减退同时伴有自杀倾向。近年来研究发现,中央杏仁核可以释放缩宫素,抑制恐惧反应,降低焦虑水平[13]。缩宫素能够调控下丘脑-垂体-肾上腺轴的活性,减少肾上腺皮质激素释放激素的分泌,发挥抗焦虑抑郁作用。另外,缩宫素能够基于雌激素受体β的作用,间接减少焦虑症状[14]。
临床试验发现,缩宫素可以缓解女性边缘性人格障碍(borderline personality disorder,BPD)患者的应激反应,减少患者的焦虑情绪[15]。SCANTAMBURLO等[16]发现,伴有严重抑郁倾向的焦虑症患者体内的血浆缩宫素水平与焦虑抑郁水平呈现负相关,焦虑与抑郁症患者的缩宫素还存在显著的性别差异[17]。最近的一项临床研究显示,青少年时期进行缩宫素治疗能够改善早期生活压力诱导的焦虑[18]。动物实验研究表明,将嗜神经毒类物质1-甲基-4-苯基-1,2,3,6-四氢吡啶注射到小鼠体内,会出现缩宫素含量降低以及焦虑感加强的现象,补充缩宫素后可明显改善上述焦虑行为[19]。MANTELLA等[20]报道,缩宫素基因敲除的雌性小鼠在高架迷宫开臂中的时间少于对照组小鼠,提示敲除缩宫素基因或许能够诱发焦虑,同时,WIGTON等[21]利用侧脑室注射缩宫素受体拮抗剂也验证这一结论。可见,焦虑抑郁与缩宫素有着密不可分的关系。
SCZ是一种复杂的中枢神经系统疾病,患者往往会呈现严重的社会认知功能障碍。研究发现,SCZ患者脑内杏仁核、前额叶等区域的异常激活能够引起缩宫素含量改变,引发社会认知功能障碍,此外缩宫素系统功能失调还能够引发脉冲前抑制(pre pulse inhibition,PP),加重精神分裂[22]。NAKATA等[23]发现,缩宫素受体基因上的单核苷酸多态性Rs53576也可影响SCZ患者的社会认知能力。更为惊喜的是缩宫素对认知存在性别差异性的影响,这一差异可能与雌激素调节缩宫素的转录激活密切相关[14]。缩宫素除了可以改善社会认知外,WIGTON等[24]还发现缩宫素能明显活化SCZ患者左侧脑岛,加强厌恶情绪识别,如经鼻给予缩宫素还能改善SCZ的嗅觉识别功能[25]。但并不是所有的研究都趋向于缩宫素都能够很好地改善SCZ,因为缩宫素临床最佳剂量仍未发现,并且缩宫素改善临床症状的机制也尚未明确。总之,缩宫素与SCZ具有相关性,但该领域仍旧存在诸多疑点,还需要进一步探究。
孤独症又称自闭症,由表观遗传因素导致,表现出社会交往障碍以及兴趣狭窄和刻板等行为。近年来,关于缩宫素系统能够调节哺乳动物社会行为进而改善自闭症相关报道越来越多。
研究发现,缩宫素受体基因的DNA甲基化会导致自闭症患者社会认知缺陷,而脑内小细胞缩宫素神经元表现出更高的自闭症风险[26,27]。在表观遗传水平上,缩宫素受体的DNA超甲基化使得男性自闭症患者的社会反应性降低以及奖赏区域功能紊乱[28,29]。静脉注射缩宫素能够提高自闭症患者准确分配语音以及语调情感意义的能力,这表明缩宫素能够促进自闭症患者的社会信息处理。缩宫素可提高自闭症患者的脑中边缘奖赏系统兴奋性,增强自闭症患者情绪反应[30]。KITAGAWA 等[31]通过动物实验证实了缩宫素具有有效恢复自闭症样POGZWT/Q1038R小鼠受损的社会行为。同时,自闭症风险基因Nlgn3敲除的小鼠常伴有缩宫素信号及社会新奇反应降低的现象[32],这为自闭症与缩宫素的联系提供了强力的证据。
疼痛是伤害性刺激作用于机体所产生的感觉,严重时引发恶心呕吐、丧失行动力等结果[33]。下丘脑神经肽缩宫素能够通过分布在大脑和周围的缩宫素受体对疼痛处理产生调节作用[34],机体产生疼痛刺激也可以影响脑内缩宫素的含量[35]。
研究发现,蛛网膜下腔等脑室注射缩宫素可以减轻痛觉神经反射,缓解腰痛[36],还可以抑制三叉神经元的伤害感受器,缓解慢性偏头痛[37]、慢性盆腔痛、水泡伤口等疼痛[38,39,40]。HASAN等[41]研究表明,谷氨酸释放后,囊泡谷氨酸转运体能够促进谷氨酸与PVN中的缩宫素共同释放到脑干和脊髓中的感觉神经元,通过抑制感觉神经元的活性来调节疼痛。胡灵洁等[42]在大鼠中央杏仁核与伏隔核中直接注射缩宫素提高了动物的疼痛阈值,表明缩宫素具有良好的镇痛作用[43]。缩宫素发挥阵痛作用与γ-氨基丁酸(GABA)能神经递质、辣椒素受体(transient receptor potential vanilloid 1,TRPV1)密不可分。一方面,缩宫素通过刺激GABA能神经元增强镇痛效果[42,44],另一方面,缩宫素可敲除TRPV1,减弱镇痛效果[45,46],这些研究都为缩宫素调节疼痛机制提供了有力证据。
酒精性精神和行为障碍是一种临床常见病,严重的患者会有身体损伤,伴有脾气暴躁、萎靡不振、思想无法集中等临床症状。目前发现,缩宫素或许能够作用于酒精依赖及使用障碍。
临床研究发现,在雄性酒精依赖大鼠和男性酒精依赖患者中会产生缩宫素明显减少和缩宫素受体结合位点增加的现象,经鼻给予缩宫素能够减少人类的酒精戒断症状和渴求[47]。另外一项小型随机、双盲临床试验同样验证缩宫素确实能显著降低酒精使用障碍(alcohol use disorders,AUD)患者的戒断症状[48]。另外,向AUD患者体内给予缩宫素与同等剂量的安慰药比较,给予缩宫素的患者戒断得分较低,同时饮酒天数和日饮酒次数也有显著下调[49]。BOWEN等[50]通过动物实验进一步印证了缩宫素降低Wistar大鼠自愿饮酒的次数,增加体内GABA能活性,从而改善酒精依赖性实验鼠的线索刺激和应急刺激的恢复[51,52]。可见,神经肽缩宫素已成为酒精使用障碍等疾病的潜在治疗选择。
学习记忆是人类最重要的认知行为,学习与记忆相辅相成。目前多项实验结果显示,缩宫素能够作用于动物和人类的学习与记忆活动的脑区。
一项临床随机双盲试验表明,鼻内给予缩宫素能够对积极反馈与消极反馈产生等效反应,提高错误意识,从而促进学习记忆[53]。同时,缩宫素在人脸识别任务中能够影响记忆生成,但不影响知觉过程,这项研究也首次揭示了缩宫素对人脸记忆影响的性别差异[54]。GARD等[55]向大鼠脑室注射缩宫素,观察到大鼠对新物体的识别能力提高,脑室注射缩宫素拮抗剂或基因敲除时,实验鼠出现社会识别能力衰退的现象[56],沉默基底前脑脑区缩宫素受体还会伴有学习记忆的损伤[57]。JANKOWSKA 等[58]发现,缩宫素可以显著抑制海马中糖原合成酶激酶-3的升高,治疗记忆障碍和神经退行性变。TAKAHASHI等[59]表明,缩宫素能够逆转β-淀粉样蛋白25-35诱导的小鼠大脑海马突触可塑性的损伤,改善学习记忆功能。最新的一项动物实验首次阐明鼻内缩宫素对氯化铝诱导的雌性大鼠阿尔茨海默病模型具有潜在的治疗作用[60]。上述研究表明,缩宫素可能参与了动物和人类的学习记忆加工过程。
目前,缩宫素及其类似物主要广泛应用于临床产科,作为人工合成的缩宫素激动剂——卡贝托星,具有良好的热稳定性,它可以有效激动子宫平滑肌中的缩宫素受体,刺激子宫强烈收缩进而加快产程,同时也可以预防产后大出血[61,62]。阿托西班是一种混合性拮抗剂(加压素V1A/缩宫素),抑制子宫收缩,在我国常用于早产的治疗[63]。有些缩宫素类似物不仅应用于产科,也可以通过减少脂肪生成、促进脂肪代谢、提高体外受精、增强心肌细胞活力来治疗肥胖症和心血管等疾病[64]。另外,非肽类缩宫素受体激动剂Cpd A、Cpd B及其盐酸盐能逆转地卓西平引起的惊吓的弱刺激抑制缺陷,而惊吓的弱刺激抑制是衡量精神类疾病的标志,这从侧面印证类缩宫素药物可以应用于精神类疾病的治疗与预防[64]。缩宫素受体的选择性激动剂([Thr4Gly7]-oxytocin,TGOT [65]),可以激活星形胶质细胞,在疼痛以及焦虑治疗中发挥作用。
越来越多的证据表明,缩宫素不仅能够作用于外周区域,也能够调节中枢神经区域发挥抗焦虑、抗抑郁、治疗酒精依赖、缓解疼痛以及改善记忆等作用。其中,缩宫素对疼痛和焦虑具有重要调节作用,已经作为潜在的镇痛和抗焦虑药物得到关注,但目前应用尚存缺陷,还需要更深入的研究。总之,缩宫素及其类似物已在中枢神经系统疾病的治疗中崭露头角,为日后缩宫素的广泛应用带来希望。
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Social dysfunction is a core symptom of many psychiatric disorders and current medications have little or no remedial effects on this. Following on from extensive studies on animal models demonstrating that the neuropeptide oxytocin plays an important role in social recognition and bonding, human-based research has explored its therapeutic potential for social dysfunction in psychiatric disorders. Here we outline the historical background of this human-based research and some of the current methodological challenges it is facing. To date, research has primarily attempted to establish functional effects through measuring altered endogenous concentrations, observing effects of exogenous administration and by investigating the effects of polymorphisms and epigenetic modifications of the oxytocin receptor gene. We summarize some of the key findings on behavioral and neural effects that have been reported in healthy subjects in the context of social cognition which have provided encouragement that oxytocin could represent a promising therapeutic target. At the same time, we have identified a number of key areas where we urgently need further information about optimal dosing strategies and interactions with other peptide and transmitter systems. Finally, we have summarized current translational findings, particularly in the context of therapeutic outcomes of intranasal oxytocin administration in autism and schizophrenia. These clinical findings while somewhat varied in outcome do offer increasing cause for optimism that targeting the oxytocin system may provide a successful therapeutic approach for social dysfunction. However, future research needs to focus on the most effective treatment strategy and which types of individuals are likely to benefit most.
DOI:10.1007/7854_2017_19
PMID:28864976
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The neuropeptide oxytocin is an important regulator of social behavior and is widely considered to reduce anxiety-related behaviors. However, growing evidence suggests that sometimes oxytocin increases anxiety. How can the same molecule have such different effects on behavior? Here we provide evidence that oxytocin produced outside of the hypothalamus is necessary and sufficient for stress-induced social anxiety behaviors. This suggests that the diverse effects of oxytocin on anxiety-related behaviors are mediated by circuit-specific oxytocin action.
[本文引用:1]
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Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug. Copyright © 2020 by The Author(s).
DOI:10.1124/pr.120.019398
PMID:32912963
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Oxytocin is a neuropeptide involved in animal and human reproductive and social behavior. Three oxytocin signaling genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (oxytocin secretion). Here, we characterized the distribution of OXT, OXTR, and CD38 mRNA across the human brain by creating voxel-by-voxel volumetric expression maps, and identified putative gene pathway interactions by comparing gene expression patterns across 20,737 genes. Expression of the three selected oxytocin pathway genes was enriched in subcortical and olfactory regions and there was high co-expression with several dopaminergic and muscarinic acetylcholine genes, reflecting an anatomical basis for critical gene pathway interactions. fMRI meta-analysis revealed that the oxytocin pathway gene maps correspond with the processing of anticipatory, appetitive, and aversive cognitive states. The oxytocin signaling system may interact with dopaminergic and muscarinic acetylcholine signaling to modulate cognitive state processes involved in complex human behaviors.
DOI:10.1038/s41467-019-08503-8
PMID:30737392
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Cerebrospinal fluid and plasmatic levels of oxytocin (OT) have been found to change in mood disorders. In post-mortem studies, the numbers of OT-expressing neurons in the paraventricular nucleus have been reported to be increased. Moreover, OT is considered as an endogenous antistress hormone. It has also revealed antidepressive effects. OT may contribute to the dysregulation of the HPA system in major depression. The aim of the study was to assess a possible relationship between anxiety and plasma oxytocin (OT) levels in depressive patients. Severity of depression was estimated with the Hamilton Depression Rating Scale and anxiety by using the Spielberger State-Anxiety Inventory. Results showed a significant negative correlation between oxytocin and the scored symptoms depression (r=-0.58, p=0.003) and anxiety (r=-0.61, p=0.005).
DOI:10.1016/j.psyneuen.2007.01.009
PMID:17383107
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Early life stress (ELS) is associated with perturbed neural development and augmented vulnerability to mental health disorders, including addiction. How ELS changes the brain to increase addiction risk is poorly understood, and there are no therapies which target this ELS-induced vulnerability. ELS disrupts the oxytocin system, which can modulate addiction susceptibility, suggesting that targeting the oxytocin system may be therapeutic in this ELS-addiction comorbidity. Therefore, we determined whether adolescent oxytocin treatment after ELS could: (1) reduce vulnerability to anxiety, social deficits, and methamphetamine-taking and reinstatement; and (2) restore hypothalamic oxytocin and corticotropin-releasing factor expressing neurons and peripheral oxytocin and corticosterone levels. Long Evans pups underwent maternal separation (MS) for either 15 min or 360 min on postnatal days (PND) 1-21. During adolescence (PNDs 28-42), rats received a daily injection of either oxytocin or saline. In Experiment 1, adult rats were assessed using the elevated plus-maze, social interaction procedure, and methamphetamine self-administration procedure, including extinction, and cue-, methamphetamine- and yohimbine-induced reinstatement. In Experiment 2, plasma for enzyme immunoassays and brain tissue for immunofluorescence were collected from adult rats after acute stress exposure. Adolescent oxytocin treatment ameliorated ELS-induced anxiety and reduced methamphetamine- and yohimbine-induced reinstatement in both sexes, and suppressed methamphetamine intake and facilitated extinction in males only. Additionally, adolescent oxytocin treatment after ELS restored oxytocin-immunoreactive cells and stress-induced oxytocin levels in males, and attenuated stress-induced corticosterone levels in both sexes. Adolescent oxytocin treatment reverses some of the ELS effects on later-life psychopathology and vulnerability to addiction. © 2022. The Author(s).
DOI:10.1038/s41386-022-01336-y
PMID:35581382
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Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.
DOI:10.3233/JAD-191091
PMID:32083584
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Previous studies have suggested that oxytocin (OT) may be anxiolytic in female laboratory rats and mice. The elevated plus-maze was used to compare anxiety-related behaviors of OT-deficient (OT-/-) and wild-type (OT+/+) mice. Female OT-/- mice displayed increased anxiety-related behavior compared with OT+/+ mice. The percentage of entries (P < 0.0002) and time spent (P < 0.003) in the open arms was less in female OT-/- than OT+/+ mice. Administration of synthetic OT, 2 ng by intracerebroventricular (icv) injection to female OT-/- mice, increased the percentage of entries (P < 0.003) and time spent (P < 0.004) in the open arms compared with artificial cerebrospinal fluid female OT-/- mice. Administration of an OT receptor antagonist (Atosiban, d[Dtyr(Et)(2), Thr(4)]ornithine vasotocin) 100 ng icv, to female OT+/+ mice increased anxiety-related behavior by decreasing the percentage of entries (P < 0.01) and time spent (P < 0.04) in the open arms compared with artificial cerebrospinal fluid-treated controls. Central infusion of an OT receptor antagonist, 100 ng icv, before administration of synthetic OT, 2 ng icv, in female OT-/- mice blocked the anxiolytic affect of OT. In contrast, male OT-/- mice displayed decreased anxiety-related behavior compared with male OT+/+ mice. The percentage of entries (P < 0.007) and time spent (P < 0.004) in the open arms was greater in male OT-/- vs. OT+/+ mice. Our findings indicate that OT pathways play a role in modulating anxiety in female mice of the C57BL/6 background, and the effect is mediated by the OT receptor.
PMID:12746288
[本文引用:1]
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| [21] |
Oxytocin is believed to attenuate the response of the hypothalamic-pituitary-adrenal axis to stress and to be anxiolytic. Stressors with a psychological component evoke both central and peripheral secretion of oxytocin in laboratory rodents. Oxytocin gene deletion mice provide a novel way to understand the role of oxytocin in stress and anxiety-related behaviours. We present our experience with female oxytocin deficient mice that were tested in an elevated plus maze (EPM), a behavioural test of anxiety, or exposed to psychogenic stressors (platform shaker or novel environment). Oxytocin-deficient mice not only displayed more anxiety-related behaviour, but also released more corticosterone after a psychogenic stressor and manifested greater stress-induced hyperthermia compared to wild-type mice. The diurnal variation of corticosterone and the response of corticosterone to corticotropin-releasing factor were not significantly different between genotypes. We also measured Fos-immunoreactive protein, an index of neuronal activation, in the medial amygdala of female mice after EPM testing. The medial amygdala is important for processing of psychogenic stress and anxiety and also contains oxytocin pathways and oxytocin receptors. The expression of Fos in the medial amygdala of mice not exposed to the EPM was not different between genotypes. Following EPM exposure, Fos expression was greater in oxytocin null compared to wild-type mice. Our findings support the hypothesis that central oxytocin is anxiolytic, and attenuates the stress response to psychogenic provocation in female mice.
PMID:15089969
[本文引用:1]
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| [22] |
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| [23] |
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| [24] |
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| [25] |
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| [26] |
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| [27] |
Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies. Copyright © 2020 Elsevier Inc. All rights reserved.
DOI:10.1016/j.neuron.2020.10.002
PMID:33113347
[本文引用:1]
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| [28] |
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| [29] |
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| [30] |
Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD. In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes. Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards. The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.
DOI:10.1186/s11689-018-9228-y
PMID:29587625
[本文引用:1]
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| [31] |
Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.
[本文引用:1]
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| [32] |
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| [33] |
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| [34] |
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| [35] |
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| [36] |
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| [37] |
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| [38] |
There is an ongoing debate whether the neuropeptide oxytocin (OT) modulates pain processing in humans. This study differentiates behavioral and neuronal OT effects on pain perception and pain anticipation by using a Pavlovian conditioning paradigm. Forty-six males received intranasally administered OT in a randomized, double-blind, placebo-controlled group design. Although OT exerted no direct effect on perceived pain, OT was found to modulate the blood oxygen level-dependent response in the ventral striatum for painful versus warm unconditioned stimuli and to decrease activity in the anterior insula (IS) with repeated thermal pain stimuli. Regarding pain anticipation, OT increased responses to CS versus CS in the nucleus accumbens. Furthermore, in the OT condition increased correct expectations, particularly for the most certain conditioned stimuli (CS)-unconditioned stimuli associations (CS and CS) were found, as well as greatest deactivations in the right posterior IS in response to the least certain condition (CS) with posterior IS activity and correct expectancies being positively correlated. In conclusion, OT seems to have both a direct effect on pain processing via the ventral striatum and by inducing habituation in the anterior IS as well as on pain anticipation by boostering associative learning in general and the neuronal conditioned fear of pain response in particular. PERSPECTIVE: The neuropeptide OT has recently raised the hope to offer a novel avenue for modulating pain experience. This study found OT to modulate pain processing and to facilitate the anticipation of pain, inspiring further research on OT effects on the affective dimension of the pain experience. Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.
DOI:S1526-5900(18)31052-6
PMID:31009765
[本文引用:1]
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| [39] |
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| [40] |
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| [41] |
Oxytocin (OT) release by axonal terminals onto the central nucleus of the amygdala exerts anxiolysis. To investigate which subpopulation of OT neurons contributes to this effect, we developed a novel method: virus-delivered genetic activity-induced tagging of cell ensembles (vGATE). With the vGATE method, we identified and permanently tagged a small subpopulation of OT cells, which, by optogenetic stimulation, strongly attenuated contextual fear-induced freezing, and pharmacogenetic silencing of tagged OT neurons impaired context-specific fear extinction, demonstrating that the tagged OT neurons are sufficient and necessary, respectively, to control contextual fear. Intriguingly, OT cell terminals of fear-experienced rats displayed enhanced glutamate release in the amygdala. Furthermore, rats exposed to another round of fear conditioning displayed 5-fold more activated magnocellular OT neurons in a novel environment than a familiar one, possibly for a generalized fear response. Thus, our results provide first evidence that hypothalamic OT neurons represent a fear memory engram. Copyright © 2019 Elsevier Inc. All rights reserved.
DOI:S0896-6273(19)30386-1
PMID:31104950
[本文引用:1]
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| [42] |
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| [43] |
Oxytocin is a neuropeptide important for social behaviors such as maternal care and parent-infant bonding. It is believed that oxytocin receptor signaling in the brain is critical for these behaviors, but it is unknown precisely when and where oxytocin receptors are expressed or which neural circuits are directly sensitive to oxytocin. To overcome this challenge, we generated specific antibodies to the mouse oxytocin receptor and examined receptor expression throughout the brain. We identified a distributed network of female mouse brain regions for maternal behaviors that are especially enriched for oxytocin receptors, including the piriform cortex, the left auditory cortex, and CA2 of the hippocampus. Electron microscopic analysis of the cerebral cortex revealed that oxytocin receptors were mainly expressed at synapses, as well as on axons and glial processes. Functionally, oxytocin transiently reduced synaptic inhibition in multiple brain regions and enabled long-term synaptic plasticity in the auditory cortex. Thus modulation of inhibition may be a general mechanism by which oxytocin can act throughout the brain to regulate parental behaviors and social cognition. Copyright © 2016 the authors 0270-6474/16/362517-19$15.00/0.
DOI:10.1523/JNEUROSCI.2409-15.2016
PMID:26911697
[本文引用:1]
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| [44] |
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| [45] |
Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
DOI:S2211-1247(17)31511-5
PMID:29117570
[本文引用:1]
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| [46] |
Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of λ-carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABAAreceptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.
[本文引用:1]
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| [47] |
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| [48] |
The neuropeptide, oxytocin (OT), has been reported to block tolerance formation to alcohol and decrease withdrawal symptoms in alcohol-dependent rodents. Numerous recent studies in human subjects indicate that OT administered by the intranasal route penetrates into and exerts effects within the brain. In a randomized, double-blind clinical trial, intranasal OT (24 IU/dose, N = 7) or placebo (N = 4) was given twice daily for 3 days in alcohol-dependent subjects admitted to a research unit for medical detoxification using Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score-driven PRN administration of lorazepam. Subjects rated themselves on the Alcohol Withdrawal Symptom Checklist (AWSC) each time CIWA scores were obtained. Subjects also completed the Penn Alcohol Craving Scale, an Alcohol Craving Visual Analog Scale (ACVAS) and the Profile of Mood States (POMS) on inpatient days 2 and 3. All subjects had drunk heavily each day for at least 2 weeks prior to study and had previously experienced withdrawal upon stopping/decreasing alcohol consumption. OT was superior to placebo in reducing alcohol withdrawal as evidenced by: less total lorazepam required to complete detoxification (3.4 mg [4.7, SD] vs. 16.5 [4.4], p = 0.0015), lower mean CIWA scores on admission day 1 (4.3 [2.3] vs. 11.8 [0.4], p < 0.0001) and day 2 (3.4 [2.2] vs. 11.1 [3.6], p < 0.002), lower AWSC scores on days 1 and 2 (p < 0.02; p = 0.07), and lower ACVAS ratings (p = 0.01) and lower POMS Tension/Anxiety subscale scores on day 2 (p < 0.01). This is the first demonstration that OT treatment may block alcohol withdrawal in human subjects. Our results are consistent with previous findings in rodents that OT inhibits neuroadaptation to and withdrawal from alcohol. OT could have advantages over benzodiazepines in managing alcohol withdrawal because it may reverse rather than maintain sedative-hypnotic tolerance. It will be important to test whether OT treatment is effective in reducing drinking in alcohol-dependent outpatients. Copyright © 2012 by the Research Society on Alcoholism.
DOI:10.1111/j.1530-0277.2012.01958.x
PMID:23025690
[本文引用:1]
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| [49] |
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| [50] |
Even moderate doses of alcohol can cause considerable motor impairment. This effect has been linked to ethanol-induced potentiation of GABA actions at δ subunit-containing GABA A receptors (δ-GABA A Rs). Here, we demonstrate that the neuropeptide oxytocin selectively attenuates ethanol-induced motor impairment in rats as well as ethanol-induced potentiation of GABAergic activity at δ-GABA A Rs. This effect of oxytocin is shown to be independent of the oxytocin receptor (OTR) and involves a direct action at δ-GABA A Rs. To our knowledge, this study provides the first evidence of oxytocin having a direct, non-OTR–mediated effect on GABA–ethanol interactions. Recent preclinical and clinical studies indicate that oxytocin may also attenuate alcohol consumption, craving, and withdrawal, and the present study shows a previously unidentified mechanism through which some of these effects may occur.
[本文引用:1]
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| [51] |
Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol-dependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([I]OVTA binding), and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol-dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positively affect treatment outcomes in alcoholics.
DOI:10.1038/npp.2017.257
PMID:29090683
[本文引用:1]
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| [52] |
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| [53] |
Feedback evaluation of actions and error response detection are critical for optimizing behavioral adaptation. Oxytocin can facilitate learning following social feedback but whether its effects vary as a function of feedback valence remains unclear. The present study aimed to investigate whether oxytocin would influence responses to positive and negative feedback differentially or equivalently. The present study employed a randomized, double-blind, placebo controlled within-subject design to investigate whether intranasal oxytocin (24 IU) influenced behavioral and evoked electrophysiological potential responses to positive or negative feedback in a probabilistic learning task. Results showed that oxytocin facilitated learning and this effect was maintained in the absence of feedback. Using novel stimulus pairings, we found that oxytocin abolished bias towards learning more from negative feedback under placebo by increasing accuracy for positively reinforced stimuli. Oxytocin also decreased the feedback-related negativity difference (negative minus positive feedback) during learning, further suggesting that it rendered the evaluation of positive and negative feedback more equivalent. Additionally, post-learning oxytocin attenuated error-related negativity amplitudes but increased the late error positivity, suggesting that it may lower conflict detection between actual errors and expected correct responses at an early stage of processing but at a later stage increase error awareness and motivation for avoiding them. Oxytocin facilitates learning and subsequent performance by rendering the impact of positive relative to negative feedback more equivalent and also by reducing conflict detection and increasing error awareness, which may be beneficial for behavioral adaption.
DOI:10.1177/0269881120972347
PMID:33274683
[本文引用:1]
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| [54] |
Oxytocin has been shown to affect human social information processing including recognition memory for faces. Here we investigated the neural processes underlying the effect of oxytocin on memorizing own-race and other-race faces in men and women. In a placebo-controlled, double-blind, between-subject study, participants received either oxytocin or placebo before studying own-race and other-race faces. We recorded event-related potentials (ERPs) during both the study and recognition phase to investigate neural correlates of oxytocin's effect on memory encoding, memory retrieval, and perception. Oxytocin increased the accuracy of familiarity judgments in the recognition test. Neural correlates for this effect were found in ERPs related to memory encoding and retrieval but not perception. In contrast to its facilitating effects on familiarity, oxytocin impaired recollection judgments, but in men only. Oxytocin did not differentially affect own-race and other-race faces. This study shows that oxytocin influences memory, but not perceptual processes, in a face recognition task and is the first to reveal sex differences in the effect of oxytocin on face memory. Contrary to recent findings in oxytocin and moral decision making, oxytocin did not preferentially improve memory for own-race faces. Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI:10.1016/j.psyneuen.2013.04.002
PMID:23648370
[本文引用:1]
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| [55] |
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| [56] |
The development of social familiarity in rodents depends predominantly on olfactory cues and can critically influence reproductive success. Researchers have operationally defined this memory by a reliable decrease in olfactory investigation in repeated or prolonged encounters with a conspecific. Brain oxytocin (OT) and vasopressin (AVP) seem to modulate a range of social behaviour from parental care to mate guarding. Pharmacological studies indicate that AVP administration may enhance social memory, whereas OT administration may either inhibit or facilitate social memory depending on dose, route or paradigm. We found that male mice mutant for the oxytocin gene (Oxt-/-) failed to develop social memory, whereas wild-type (Oxt+/+) mice showed intact social memory. Measurement of both olfactory foraging and olfactory habituation tasks indicated that olfactory detection of non-social stimuli is intact in Oxt-/- mice. Spatial memory and behavioural inhibition measured in a Morris water-maze, Y-maze, or habituation of an acoustic startle also seemed intact. Treatment with OT but not AVP rescued social memory in Oxt-/- mice, and treatment with an OT antagonist produced a social amnesia-like effect in Oxt+/+ mice. Our data indicate that OT is necessary for the normal development of social memory in mice and support the hypothesis that social memory has a neural basis distinct from other forms of memory.
PMID:10888874
[本文引用:1]
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| [57] |
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| [58] |
Alzheimer’s disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3&#946;) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3&#946; inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological and clinical profiles need to be defined.
[本文引用:1]
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| [60] |
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| [61] |
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| [62] |
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