Neuropharmacology最新文献_第7页

Dentate gyrus microglial dynamics contributes to high-fat diet-induced depression-like behaviors in mice. 齿状回小胶质动力学有助于小鼠高脂肪饮食诱导的抑郁样行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-27 DOI: 10.1016/j.neuropharm.2026.110893

Tao Zhu, Minxiu Ye, Chao Huang, Yilong Jiang, Yiming Gu, Ziwei Cao, Feng Xu, Jianbin Su, Rongrong Yang

High-fat diet (HFD) consumption is a harmful habit worldwide that can lead to various problems, including an increased risk of depression. However, the mechanisms underlying HFD-induced depression remain unclear. Previous studies have reported that a decline in microglia in the dentate gyrus, following initial microglial activation under stress, is an important mechanism mediating the pathogenesis of depression. As HFD can activate microglia, we hypothesize that dynamic changes in dentate gyrus microglia also mediate the development of depression-like behaviors under chronic HFD exposure. Our results showed that a 12-week HFD induced depression-like behaviors in mice, accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus. The reduction in microglia in the dentate gyrus of mice treated with a 12-week HFD was mediated by initial microglial activation and subsequent microglial damage. Suppressing initial microglial activation with minocycline prevented HFD-induced dentate gyrus microglial damage and decline, as well as the development of depression-like behaviors in HFD-treated mice. Furthermore, administration of lipopolysaccharide (LPS), a classical microglial stimulant that restored the number of microglia in the dentate gyrus of HFD mice, reversed the depression-like behaviors in mice given a 12-week HFD. These findings reveal a dynamic microglial response in the dentate gyrus underlying HFD-induced depression-like behaviors and suggest that modulating microglial dynamics may offer a potential strategy for preventing or treating depression caused by factors associated with high fat intake.

在世界范围内，高脂肪饮食是一种有害的习惯，会导致各种问题，包括增加患抑郁症的风险。然而，hfd诱发抑郁症的机制尚不清楚。先前的研究报道，应激下初始小胶质细胞激活后，齿状回小胶质细胞的下降是介导抑郁症发病的重要机制。由于HFD可以激活小胶质细胞，我们假设齿状回小胶质细胞的动态变化也介导了慢性HFD暴露下抑郁样行为的发展。我们的研究结果表明，12周的HFD诱导小鼠抑郁样行为，并伴有齿状回小胶质细胞的显著减少和营养不良。经12周HFD处理的小鼠齿状回小胶质细胞的减少是由初始小胶质细胞激活和随后的小胶质细胞损伤介导的。二甲胺四环素抑制初始小胶质细胞激活，可防止hfd诱导的齿状回小胶质细胞损伤和衰退，以及hfd治疗小鼠抑郁样行为的发生。此外，脂多糖（LPS）是一种经典的小胶质细胞兴奋剂，可以恢复HFD小鼠齿状回中小胶质细胞的数量，逆转了给予12周HFD小鼠的抑郁样行为。这些发现揭示了hfd诱导的抑郁样行为背后齿状回的动态小胶质反应，并表明调节小胶质动力学可能为预防或治疗高脂肪摄入相关因素引起的抑郁症提供了一种潜在的策略。

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引用次数: 0

Oxytocin may promote hippocampal neurogenesis in ischemic stroke rats via a pathway related to DNMT1-mediated Wnt3a/β-catenin 催产素可能通过dnmt1介导的Wnt3a/β-catenin通路促进缺血性脑卒中大鼠海马神经发生

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-26 DOI: 10.1016/j.neuropharm.2025.110785

Xiaofan Li , Guang Shi , Wanshu Guo , Kaishu Wen , Yifei Liu , Jiayue Cheng , Meichi Liu , Yuehui Yang , Xinyu Fan

DNA methylation plays a pivotal role in neuroprotection after ischemic stroke. Oxytocin, a neuropeptide renowned for its involvement anti-inflammatory and antioxidant activities, emerges as a promising candidate for the treatment of stroke. Here, we employed a transient middle cerebral artery occlusion (tMCAO) rat model to explore the underlying mechanisms of oxytocin's therapeutic potential. We utilized the Morris Water Maze, novel object recognition, and intruder tests to assess spatial memory, cognitive memory, and social memory abilities in rats, respectively. RNA sequencing and Western blotting were employed to detect alterations in mRNA expression and protein expression levels in the hippocampus. Daily oxytocin administration (0.1 and 1.0 mg/kg, subcutaneous) for seven days significantly reduced infarct volume, restored the expression of 1100 genes, including NQO1 and HO1, and robustly promoted hippocampal neurogenesis in tMCAO rats. These effects translated into enhanced neurological function and improved learning and memory abilities. Remarkably, our findings reveal that oxytocin-induced neurogenesis is intimately linked to the activation of the Wnt3a/β-catenin signaling pathway with Nrf2 as a key downstream target. Furthermore, it is possible that oxytocin, acting through its receptors, inhibited the tMCAO-induced binding of DNMT1 to MeCP2, thereby preventing the increase in DNA methylation at the Wnt3a gene. In summary, our study implies a possible involvement of oxytocin in the activation of the DNMT1-mediated Wnt3a/β-catenin signaling pathway. It may contribute to enhancing hippocampal neurogenesis and ameliorating memory impairments in rats with ischemic stroke. This hints that oxytocin holds great promise as a potential therapeutic agent for promoting post-stroke neurogenesis.

DNA甲基化在缺血性脑卒中后的神经保护中起关键作用。催产素是一种神经肽，因其抗炎和抗氧化活性而闻名，是治疗中风的有希望的候选者。本研究采用短暂性大脑中动脉闭塞（tMCAO）大鼠模型来探讨催产素治疗潜力的潜在机制。利用Morris水迷宫、新物体识别和入侵者测试分别评估大鼠的空间记忆、认知记忆和社会记忆能力。采用RNA测序和Western blotting检测海马组织mRNA和蛋白表达水平的变化。每天给予催产素（0.1和1.0 mg/kg，皮下注射）7天后，可显著减少脑梗死体积，恢复NQO1和HO1等1100个基因的表达，并显著促进tMCAO大鼠海马神经发生。这些效果转化为增强的神经功能和改善的学习和记忆能力。值得注意的是，我们的研究结果表明，催产素诱导的神经发生与Wnt3a/β-catenin信号通路的激活密切相关，Nrf2是一个关键的下游靶点。此外，催产素可能通过其受体作用，抑制了tmcao诱导的DNMT1与MeCP2的结合，从而阻止了Wnt3a基因DNA甲基化的增加。总之，我们的研究提示催产素可能参与dnmt1介导的Wnt3a/β-catenin信号通路的激活。它可能有助于促进缺血性脑卒中大鼠海马神经发生和改善记忆障碍。这暗示催产素作为促进中风后神经发生的潜在治疗剂具有很大的前景。

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引用次数: 0

Cyclooxygenase 2 (COX-2) expression is elevated in prefrontal cortex neurons, not microglia, following methamphetamine self-administration in male and female rats 在雄性和雌性大鼠自我服用甲基苯丙胺后，环氧合酶2 （COX-2）在前额皮质神经元中的表达升高，而不是小胶质细胞。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-21 DOI: 10.1016/j.neuropharm.2025.110778

Amanda M. Acuña , Rebecca Whittington , Emma Peacock , Serena E. Rodarte , Justin L. Legg , Erin K. Nagy , Annabel Carlson , Hiba Siddiqui , Julie W. Karugu , M. Foster Olive

Methamphetamine (METH) use produces lasting elevations in peripheral and central inflammation that correspond to cognitive and behavioral deficits, which may contribute to the likelihood of relapse. Though a great deal of research over the last few decades has attempted to investigate pharmacotherapies to help facilitate long term abstinence from METH, there are still no FDA approved medications to treat METH use disorders. Our laboratory recently showed that markers of neuroinflammation persist three weeks into abstinence following prolonged (96 h/week for 3 weeks) access to METH self-administration. We also showed that medial prefrontal cortex (mPFC) mediated behavioral flexibility deficits observed at this timepoint are attenuated by the COX-2 inhibitor parecoxib. Given the role of microglia in central inflammatory processes, the current work utilized immunohistochemistry to determine whether COX-2 expression in microglia was elevated in the mPFC during abstinence from METH. We also sought to determine if METH-induced changes in microglial morphology could potentially be altered by COX-2 inhibition. We found that the number of COX-2 expressing cells was elevated in the mPFC of rats that self-administered METH compared to those that self-administered saline. Surprisingly, COX-2 immunoreactivity was absent in microglia but was predominantly observed in neurons. Most COX-2 immunoreactivity was detected in glutamatergic neurons in both sexes, while males exhibited a reduction in COX-2 expression in GABAergic neurons. COX-2 immunoreactivity was frequently absent from the infralimbic and cingulate cortices and was therefore not analyzed. Paired with our prior findings that COX-2 inhibition attenuates METH-induced behavioral deficits known to be mediated by the mPFC, these results suggest that altered neuronal COX-2 expression should be investigated for its influence on METH-induced deficits in mPFC function.

甲基苯丙胺（冰毒）的使用会导致外周和中枢炎症持续升高，这与认知和行为缺陷相对应，这可能会导致复发的可能性。尽管在过去的几十年里有大量的研究试图研究药物疗法来帮助长期戒除冰毒，但仍然没有FDA批准的药物来治疗冰毒使用障碍。我们的实验室最近表明，神经炎症标志物在长期（每周96小时，持续3周）自行服用甲基苯丙胺后，持续戒断3周。我们还发现，在这个时间点观察到的内侧前额叶皮层（mPFC）介导的行为灵活性缺陷被COX-2抑制剂parecoxib减弱。鉴于小胶质细胞在中枢炎症过程中的作用，目前的工作利用免疫组织化学来确定戒除甲基安非他明期间mPFC中小胶质细胞中的COX-2表达是否升高。我们还试图确定甲基甲醚诱导的小胶质细胞形态学变化是否可能通过抑制COX-2而改变。我们发现自我服用冰毒的大鼠的mPFC中表达COX-2的细胞数量比自我服用生理盐水的大鼠高。令人惊讶的是，COX-2免疫反应性在小胶质细胞中不存在，但在神经元中主要观察到。大多数COX-2免疫反应性在两性的谷氨酸能神经元中检测到，而雄性在gaba能神经元中表现出COX-2表达减少。COX-2免疫反应性经常在边缘下和扣带皮层缺失，因此未被分析。结合我们之前的研究结果，COX-2抑制减弱了甲基醚诱导的mPFC介导的行为缺陷，这些结果表明，神经元COX-2表达的改变应该被研究其对甲基醚诱导的mPFC功能缺陷的影响。

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引用次数: 0

Prelimbic cortex, but not its nucleus reuniens projections, regulates punished alcohol self-administration 前边缘皮层，而不是其核的重连突起，控制着受惩罚的酒精自我管理。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-15 DOI: 10.1016/j.neuropharm.2025.110766

Maya N. Bluitt , Wen Liu , Ana C. Muñoz , Joseph M. Carew , Joyce Besheer

Alcohol use that persists despite negative consequences is observed in only a minority of those who drink alcohol and is a defining feature of alcohol use disorder (AUD). The neurobiological mechanisms underlying drinking despite negative outcomes are poorly understood. The medial prefrontal cortex (mPFC) is critical for decision-making and inhibitory control over behavior. Here, we employed a foot shock-punished alcohol self-administration procedure to examine the role of medial prefrontal subregions in drinking despite negative consequences in male Wistar rats. Introduction of response-contingent foot shock produced robust individual variability in suppression of responding, and rats were classified into shock-sensitive (SS) and shock-resistant (SR) subgroups. Using c-Fos immunohistochemistry, we showed that neuronal activation in the prelimbic (PrL) subdivision of the mPFC corresponds with suppression of responding during punished self-administration. To test the functional role of the PrL, we used chemogenetics to manipulate neuronal activity during punished sessions. Chemogenetic activation of the PrL enhanced responding during punished sessions in both SS and SR subgroups, while chemogenetic inhibition of the PrL reduced responding only in rats with an SR phenotype. We further explored how the PrL mediates punished drinking by assessing its outputs to the nucleus reuniens (Re), which plays a prominent role in aversive learning and memory. Chemogenetic activation and inhibition of PrL→Re projections had no effect on punished responding. Together, these data implicate the PrL in mediating individual differences in punished alcohol self-administration.

尽管有负面后果，但持续使用酒精的情况只出现在少数饮酒者身上，这是酒精使用障碍（AUD）的一个典型特征。尽管有负面结果，但饮酒背后的神经生物学机制尚不清楚。内侧前额叶皮层（mPFC）是决策和抑制控制行为的关键。在这里，我们采用足部电击惩罚酒精自我给药程序来检查内侧前额叶亚区在雄性Wistar大鼠饮酒中的作用，尽管有负面后果。引入反应偶发足部冲击会产生强烈的个体差异，抑制反应，并将大鼠分为冲击敏感（SS）和冲击抵抗（SR）亚组。利用c-Fos免疫组织化学，我们发现mPFC边缘前区（PrL）的神经元激活与惩罚自我给药时的反应抑制相对应。为了测试PrL的功能作用，我们使用化学遗传学来操纵惩罚过程中的神经元活动。PrL的化学发生激活增强了SS和SR亚组在惩罚过程中的反应，而PrL的化学发生抑制仅在SR表型的大鼠中降低了反应。我们进一步探讨了PrL如何通过评估其对Re的输出来调节惩罚性饮酒，Re在厌恶学习和记忆中起着重要作用。化学发生激活和抑制PrL→Re投射对惩罚反应无影响。综上所述，这些数据表明PrL介导了受惩罚酒精自我管理的个体差异。

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引用次数: 0

Perinatal opioid exposure alters alcohol-driven reward behaviors in adolescent male and female rats 围产期阿片类药物暴露改变青春期雄性和雌性大鼠的酒精驱动奖励行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-19 DOI: 10.1016/j.neuropharm.2025.110776

Christopher T. Searles, Meghan E. Vogt, Hannah J. Harder, Anne Z. Murphy

In the U.S., a baby is born with neonatal opioid withdrawal syndrome (NOWS) every 15 min—a rate that has increased sevenfold since 2004. Clinical studies have established intrauterine exposure to addictive drugs as a risk factor for adverse health outcomes in adolescence, including increased propensity for future illicit drug use. Despite extensive knowledge regarding common mechanisms of action in the neural circuitry that drives opioid and alcohol reward, there are limited data on the risks infants with NOWS face regarding alcohol use later in life. Our laboratory has developed a clinically relevant model for morphine exposure in rats spanning pre-conception to the first postnatal week. Using this model, we report that perinatal opioid exposure (POE) increased alcohol consumption in female rats under home cage conditions and, inversely, reduced alcohol consumption in both male and female rats in an operant conditioning paradigm. Operant responding was also reduced for sucrose, suggesting that the impact of POE on reward-seeking behaviors is not limited to addictive drugs. Parallel studies examined the effect of perinatal morphine exposure on μ-opioid receptor (MOR) expression in male and female rats at postnatal and adolescent ages. We report age and region-dependent changes in MOR within the nucleus accumbens and medial habenula, regions previously shown to play significant roles in reward/aversion circuitry. Together, our results provide novel evidence of changes in alcohol-directed reward behavior in a clinically relevant rat model of perinatal opioid exposure.

在美国，每15分钟就有一名患有新生儿阿片类药物戒断综合征（NOWS）的婴儿出生，这一比率自2004年以来增长了7倍。临床研究证实，宫内接触成瘾性药物是青春期不良健康结果的一个风险因素，包括未来非法使用药物的倾向增加。尽管对驱动阿片类药物和酒精奖励的神经回路中的共同作用机制有广泛的了解，但关于NOWS婴儿在以后的生活中面临的酒精使用风险的数据很少。我们的实验室已经开发了一个临床相关的模型吗啡暴露在大鼠从孕前到产后第一周。使用该模型，我们报告围产期阿片类药物暴露（POE）增加了家庭笼条件下雌性大鼠的酒精摄入量，相反，在操作性条件反射范式下雄性和雌性大鼠的酒精摄入量减少。蔗糖也降低了操作性反应，这表明POE对寻求奖励行为的影响不仅限于成瘾性药物。平行研究考察了围产期吗啡暴露对雌雄大鼠产后和青春期μ-阿片受体（MOR）表达的影响。我们报告了伏隔核和内侧链内MOR的年龄和区域依赖性变化，这些区域先前被证明在奖励/厌恶回路中起重要作用。总之，我们的研究结果为围产期阿片类药物暴露的临床相关大鼠模型中酒精导向奖励行为的变化提供了新的证据。

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引用次数: 0

An industrial perspective on ligand bias in GPCR drug discovery GPCR药物发现中配体偏置的工业前景

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-25 DOI: 10.1016/j.neuropharm.2025.110782

James P. Farmer , James E. Mason , Nicholas D. Holliday , Stephen J. Briddon , Leigh A. Stoddart

Since the initial identification of ligand bias in the late 1990s, the possibility of designing new clinical compounds that preferentially target select signalling pathways has been attractive to drug developers. The potential for maximising efficacy and minimising on-target side-effects at early lead optimisation stages could significantly improve the success rate of discovery programmes. However, the search for truly biased ligands poses additional challenges to the considerable existing difficulties facing any lead compound on its route to clinical licensing. As such, despite their potential advantages, the development of biased ligands has been limited within the wider pharmaceutical industry so far. Here, we give our current perspective on the landscape of biased ligand development and an overview of the wider implications that must be considered when entering a biased ligand discovery programme.

自20世纪90年代末首次发现配体偏性以来，设计优先靶向选定信号通路的新型临床化合物的可能性一直吸引着药物开发人员。在早期先导优化阶段最大化疗效和最小化靶侧副作用的潜力可以显著提高发现方案的成功率。然而，寻找真正偏颇的配体对任何先导化合物在其获得临床许可的道路上面临的相当大的困难提出了额外的挑战。因此，尽管有潜在的优势，偏置配体的发展到目前为止在更广泛的制药工业中受到限制。在这里，我们给出了我们目前对偏配体发展前景的看法，并概述了在进入偏配体发现计划时必须考虑的更广泛的影响。

引用次数: 0

P2X purinergic receptors are required for correct cortical development in human brain organoids P2X嘌呤能受体是人脑类器官皮层发育的必要条件。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-28 DOI: 10.1016/j.neuropharm.2025.110784

María Benito-León , Julia Serrano-López , Celia Llorente-Sáez , Marina Arribas-Blázquez , Luis A. Olivos-Oré , Veronica Pravata , Raquel Pérez-Sen , Esmerilda G. Delicado , Micha Drukker , Antonio R. Artalejo , Silvia Cappello , Rosa Gómez-Villafuertes , Felipe Ortega

The human neocortex represents a crucial evolutionary advance, the formation of which requires the tight and precise orchestration of both intracellular and extracellular signals. Structures grown in three-dimensional cultures, specifically human-induced pluripotent stem cells (hIPSCs)-derived cerebral organoids (COs), have been fundamental to study the signals that regulate the formation of the cortex, overcoming the limitations of 2D cultures. Amongst these, purinergic signaling driven by extracellular ATP and other nucleotides may encode crucial intercellular communications that govern central nervous system (CNS) development. The ATP that accumulates in the extracellular milieu can interact with both ionotropic P2X and metabotropic P2Y receptors on cells to exert its modulating effects. Although widely studied in different animal models, little is known about the expression and function of this signaling system in the human cortex. Thus, here we analyzed the expression of P2X receptor subunits comprehensively throughout the entire process of CO development, confirming that P2X receptors are functional in ventricular structures of the human cortex. Specifically, we detected the expression of P2X1, P2X4, and P2X6 in CO, showing distinct distributions in Nestin⁺ radial glial cells and/or DCX⁺ newborn neurons. Significantly, we also show how prolonged pharmacological inhibition of P2X activity affects CO development, resulting in smaller organoids with fewer and less well-organized cortical ventricles. Altogether, our findings point to a relevant role of purinergic signaling during the formation of the human cerebral cortex.

人类新皮层是一个重要的进化过程，它的形成需要细胞内和细胞外信号紧密而精确的协调。在三维培养物中生长的结构，特别是人类诱导的多能干细胞（hIPSCs）衍生的脑类器官（COs），已经成为研究调节皮层形成的信号的基础，克服了二维培养物的局限性。其中，由细胞外ATP和其他核苷酸驱动的嘌呤能信号可能编码控制中枢神经系统（CNS）发育的关键细胞间通讯。在细胞外环境中积累的ATP可以与细胞上的嗜离子性P2X和代谢性P2Y受体相互作用，发挥其调节作用。尽管在不同的动物模型中进行了广泛的研究，但对该信号系统在人类皮层中的表达和功能知之甚少。因此，我们全面分析了CO发育全过程中P2X受体亚基的表达，证实了P2X受体在人皮层脑室结构中的功能。具体来说，我们检测到P2X1、P2X4和P2X6在CO中的表达，在Nestin+放射状胶质细胞和/或DCX+新生神经元中有明显的分布。值得注意的是，我们还展示了P2X活性的长期药理抑制如何影响CO的发育，导致类器官更小，皮质脑室更少，组织更不完善。总之，我们的发现指出了嘌呤能信号在人类大脑皮层形成过程中的相关作用。

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引用次数: 0

Taltirelin treatment alleviates PTSD-like symptoms and restores neural oscillations in male mice receiving single prolonged stress 他替雷林治疗可减轻单次长时间应激的雄性小鼠ptsd样症状并恢复神经振荡。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-30 DOI: 10.1016/j.neuropharm.2025.110791

Keke Ding , Zhengrong Zhang , Jingwen Niu , Mingyue Zhu , Junjie Zhang , Lixia Chen , Shaojie Yang , Jingji Wang , Guoqi Zhu

Thyrotropin-releasing hormone (TRH) plays an important role in the regulation of emotion and cognition. However, whether TRH in the hippocampus participates in the development of post-traumatic stress disorder (PTSD)-like behaviors and the mechanisms involved remain unclear. Transcriptomic analysis was conducted to identify differentially expressed genes (DEGs) in the hippocampus of single prolonged stress (SPS), which is a well-known procedure inducing PTSD-like behaviors in rodents. The expression of pro-TRH and its receptor 1 (TRH-R1) in the hippocampus were assessed using Western blot. Taltirelin (TAL) were employed to examine their regulatory roles in PTSD-like behaviors and neural oscillations. In this study, transcriptomic analysis identified 63 DEGs in the hippocampus of SPS mice compared to controls. The DEGs were mainly involved in hormone activity, and regulated the pathways such as neuroactive ligand-receptor interaction. Western blotting showed that both pro-TRH and its receptor 1 (TRH-R1) were significantly decreased in the hippocampus of the SPS group compared to the control group. TAL treatment remedied PTSD-like behaviors and reversed abnormal hippocampal neural oscillations induced by SPS. Mechanistic investigations revealed that TAL reversed the SPS-induced dysregulation of synaptic proteins in the hippocampus. Together, administration of the TRH analog TAL ameliorates SPS-induced PTSD-like behaviors and restores neural oscillations in mice, probably through mechanisms involving modulation of neuronal synaptic transmission and plasticity.

促甲状腺素释放激素（TRH）在调节情绪和认知方面起着重要作用。然而，海马TRH是否参与创伤后应激障碍（PTSD）样行为的发展及其机制尚不清楚。通过转录组学分析，鉴定了单次延长应激（SPS）诱发鼠ptsd样行为的海马区差异表达基因（DEGs）。Western blot检测海马组织中pro-TRH及其受体1 （TRH-R1）的表达。应用他替雷林（Taltirelin， TAL）研究其对ptsd样行为和神经振荡的调节作用。在本研究中，转录组学分析发现，与对照组相比，SPS小鼠海马中存在63个DEGs。deg主要参与激素活性，并调节神经活性配体-受体相互作用等途径。Western blotting结果显示，与对照组相比，SPS组海马组织中pro-TRH及其受体1 （TRH-R1）均显著降低。TAL治疗可改善ptsd样行为，逆转SPS引起的海马神经异常振荡。机制研究显示，TAL逆转了sps诱导的海马突触蛋白失调。综上所述，TRH模拟物TAL改善了sps诱导的ptsd样行为，并恢复了小鼠的神经振荡，这可能是通过调节神经元突触传递和可塑性的机制实现的。

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引用次数: 0

Fluoxetine modulates both endocannabinoid and lysophosphatidic acid pathways in a region-specific Manner during alcohol withdrawal in male rats 氟西汀在雄性大鼠酒精戒断过程中以区域特异性方式调节内源性大麻素和溶血磷脂酸途径。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-19 DOI: 10.1016/j.neuropharm.2025.110773

Adriana Castro-Zavala , Kirstin Boonen , Laura Sánchez-Marín , Marisa Roberto , Francisco J. Pavón-Morón , Fernando Rodríguez de Fonseca , Antonia Serrano

Anxiety is a major symptom associated with alcohol withdrawal and a major factor increasing the risk of relapse. Although fluoxetine, a selective serotonin reuptake inhibitor, is used to alleviate these symptoms, its effects on brain lipid signaling pathways involved in withdrawal-related anxiety remain unclear. This study evaluated, in a preclinical model, the behavioral and molecular effects of chronic alcohol exposure and fluoxetine treatment during early abstinence. Male Wistar rats received oral alcohol (3 g/kg) or saline for 14 days, followed by 7 days without alcohol, during which fluoxetine (10 mg/kg) was administered to designated groups. Anxiety-like behavior was assessed using the elevated plus maze. Circulating plasma levels of corticosterone, 2-arachidonoylglycerol (2-AG), lysophosphatidic acid (LPA), and interleukin-10 (IL-10) were quantified, and gene expression analyses were performed in the amygdala and medial prefrontal cortex (mPFC). Chronic alcohol administration increased anxiety-like behavior and plasma 2-AG, while reducing LPA and IL-10 levels. Fluoxetine induced an anxiolytic effect in controls but was ineffective in alcohol-exposed rats, only normalizing the alcohol-induced increase of plasma 2-AG. At the molecular level, fluoxetine modulated gene expression region-specifically, altering 2-AG-related genes in the amygdala and enhancing LPA signaling in the mPFC. Hierarchical clustering revealed coordinated downregulation of 2-AG pathway genes in the alcohol-fluoxetine group and partial restoration of anti-inflammatory markers. These findings indicate fluoxetine modulates lipid signaling and immune-related genes during alcohol withdrawal, but its anxiolytic efficacy may be limited after alcohol exposure. These findings may contribute to the development of targeted therapeutic strategies for alcohol-related anxiety and relapse prevention.

焦虑是与酒精戒断相关的主要症状，也是增加复发风险的主要因素。尽管氟西汀（一种选择性血清素再摄取抑制剂）被用于缓解这些症状，但其对涉及戒断相关焦虑的脑脂质信号通路的影响尚不清楚。本研究在临床前模型中评估了早期戒酒期间慢性酒精暴露和氟西汀治疗的行为和分子效应。雄性Wistar大鼠连续14天口服酒精（3 g/kg）或生理盐水，随后7天不含酒精，在此期间，将氟西汀（10 mg/kg）给予指定组。焦虑样行为采用高架+迷宫进行评估。定量循环血浆皮质酮、2-花生四烯醇甘油（2-AG）、溶磷脂酸（LPA）和白介素-10 （IL-10）水平，并分析杏仁核和内侧前额叶皮层（mPFC）的基因表达。慢性酒精摄入增加了焦虑样行为和血浆2-AG，同时降低了LPA和IL-10水平。氟西汀在对照组中有抗焦虑作用，但在酒精暴露大鼠中无效，仅使酒精诱导的血浆2-AG升高正常化。在分子水平上，氟西汀特异性地调节了基因表达区域，改变了杏仁核中的2- ag相关基因，增强了mPFC中的LPA信号。分层聚类揭示了酒精-氟西汀组2-AG通路基因的协同下调和抗炎标志物的部分恢复。这些发现表明氟西汀在酒精戒断期间调节脂质信号和免疫相关基因，但其抗焦虑作用可能在酒精暴露后受到限制。这些发现可能有助于制定针对酒精相关焦虑和复发预防的靶向治疗策略。

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引用次数: 0

Increased activity of GSK3β in NAc D2-MSNs contributes to methamphetamine-induced conditioned place prefernence NAc D2-MSNs中GSK3β活性的增加有助于甲基苯丙胺诱导的条件位置偏好。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2026-02-15 Epub Date: 2025-11-22 DOI: 10.1016/j.neuropharm.2025.110774

Jincen Liu , Yue Feng , Yudian Ye , Haotian Ma , Xilin Shao , Xinyue Yan , Shuguang Wei , Peng Yan , Jianghua Lai

Glycogen synthase kinase 3β (GSK3β) in the nucleus accumbens (NAc) is implicated in drug addiction, but its specific role in methamphetamine (METH)-induced conditioned place preference (CPP), including the critical phase and the involved medium spiny neuron (MSN) subtype, remains unclear. Here, we targeted three critical phases of the CPP paradigm (acquisition, consolidation, expression) by either systemic delivering or localized intra-NAc microinjecting inhibitor of GSK3β to investigate the phase-specific roles of GSK3β in METH-induced CPP. And the effects of GSK3β on D1-/D2-type MSN activity dynamics were delineated through in vivo fiber photometry calcium imaging. Our study found that METH-paired context enhanced GSK3β activity in NAc. Systemic GSK3β suppression with lithium chloride (LiCl) attenuated METH-induced CPP across all phases, whereas intra-NAc suppression with 0.1 ng SB216763 was effective only when administered during acquisition phase. Furthermore, we identified that the METH-paired context-associated elevation in GSK3β activity predominantly localized to NAc D2-MSNs but not NAc D1-MSNs. Selective knockdown of GSK3β expression in NAc D2-MSNs attenuated METH-induced CPP by reactivating D2-MSNs coupled with concurrent suppression of D1-MSN activity. This study reveals a cell-type-specific dysregulation of GSK3β signaling in the context of METH reward processing, highlighting the contrasting roles of D1-and D2-MSNs in addiction-related plasticity.

伏隔核（NAc）中的糖原合成酶激酶3β (GSK3β)与药物成瘾有关，但其在甲基苯丙胺（METH）诱导的条件位置偏好（CPP）中的具体作用，包括关键期和所涉及的中棘神经元（MSN）亚型，目前尚不清楚。在这里，我们通过系统递送或局部nac内微注射GSK3β抑制剂，针对CPP范式的三个关键阶段（获得、巩固和表达）来研究GSK3β在甲基甲醚诱导的CPP中的阶段性作用。通过体内纤维光度法钙显像研究了GSK3β对D1-/ d2型MSN活性动力学的影响。我们的研究发现，meth配对的上下文增强了NAc中GSK3β的活性。用氯化锂（LiCl）系统性抑制GSK3β可在所有阶段减弱甲基醚诱导的CPP，而用0.1 ng SB216763抑制nac仅在获取阶段有效。此外，我们发现甲基配对上下文相关的GSK3β活性升高主要定位于NAc D2-MSNs，而不是NAc D1-MSNs。选择性敲低NAc D2-MSNs中GSK3β的表达，通过重新激活D2-MSNs并同时抑制D1-MSN活性来减弱meth诱导的CPP。本研究揭示了甲基安非他明奖励加工中GSK3β信号的细胞类型特异性失调，突出了D1-和d2 - msn在成瘾相关可塑性中的不同作用。

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