Neuropharmacology最新文献_第8页

Restorative properties of chronic lurasidone treatment on emotional dysfunction in rats exposed to chronic unavoidable stress: A role for medial prefrontal cortex - nucleus accumbens network 慢性鲁拉西酮治疗对慢性不可避免应激大鼠情绪功能障碍的恢复作用：内侧前额叶皮层-伏隔核网络的作用。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-13 DOI: 10.1016/j.neuropharm.2025.110302

Eleonora Corridori , Sara Salviati , Veronica Begni , Alessia Marchesin , Carla Gambarana , Marco Andrea Riva , Simona Scheggi

Anhedonia, a transdiagnostic symptom prevalent in depressive and psychotic disorders, poses a significant challenge for pharmacological intervention due to its association with impaired motivation. Understanding how psychotropic drugs can modulate this pathological domain and elucidating the molecular mechanisms underlying such effects are crucial endeavors in psychiatric research. In this study, we aimed to investigate the pro-motivational properties of lurasidone in a rat (Sprague Dawley males) model of anhedonia and to unravel the interplay between lurasidone and the brain regions critical for reward processing. Exposure to unpredictable chronic stress (UCS) led to a marked reduction in motivation, a deficit that was restored by lurasidone treatment at 3 mg/kg, but not at 10 mg/kg. Interestingly, the stress-induced decrease in reactivity to negative stimuli was reversed by both doses of lurasidone. At the molecular level, stressed animals exhibited reduced expression of neuroplastic markers, that was increased following lurasidone administration. Furthermore, UCS exposure impaired the activation of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) in response to hedonic stimuli, an effect amended by lurasidone treatment. Additionally, lurasidone restored the impaired phosphorylation of DARPP-32, a key regulator of dopamine signaling, in mPFC and NAc of UCS rats exposed to a hedonic stimulus.

These findings underscore the potential of lurasidone in improving various psychopathological domains, like impaired motivation and emotional reactivity, core elements contributing to the disability associated with mental disorders. These effects highlight the therapeutic potential of lurasidone in addressing the intricate behavioral and neurochemical alterations associated with anhedonia and related mood disorders.

快感缺乏是一种普遍存在于抑郁症和精神病中的跨诊断症状，由于其与动机受损相关，因此对药物干预提出了重大挑战。了解精神药物如何调节这种病理领域并阐明这种作用背后的分子机制是精神病学研究的关键努力。在这项研究中，我们旨在研究鲁拉西酮在快感缺乏大鼠（Sprague Dawley雄性）模型中的促进动机特性，并揭示鲁拉西酮与大脑奖励处理关键区域之间的相互作用。暴露于不可预测的慢性应激（UCS）导致动机显著降低，这种缺陷可以通过3 mg/kg的鲁拉西酮治疗恢复，但10 mg/kg的鲁拉西酮治疗不能恢复。有趣的是，两种剂量的鲁拉西酮都逆转了应激引起的对负刺激的反应性下降。在分子水平上，应激动物表现出神经可塑性标志物的表达降低，鲁拉西酮给药后神经可塑性标志物的表达增加。此外，UCS暴露损害了内侧前额叶皮层（mPFC）和伏隔核（NAc）对享乐刺激的反应，鲁拉西酮治疗改善了这一效应。此外，鲁拉西酮恢复了暴露于享乐刺激的UCS大鼠mPFC和NAc中受损的DARPP-32的磷酸化，DARPP-32是多巴胺信号的关键调节因子。这些发现强调了鲁拉西酮在改善各种精神病理领域的潜力，如动机受损和情绪反应性受损，这是导致精神障碍相关残疾的核心因素。这些作用突出了鲁拉西酮在解决与快感缺乏和相关情绪障碍相关的复杂行为和神经化学改变方面的治疗潜力。

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引用次数: 0

CD38-mediated oxytocin signaling in paraventricular nucleus contributes to empathic pain 室旁核中cd38介导的催产素信号与共情疼痛有关。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-13 DOI: 10.1016/j.neuropharm.2025.110301

Xinying Zhang , Zifeng Wu , Siqi Yang , Yuanyuan Wang , Suwan Hu , Yawei Ji , Qi Zhang , Yuchen Bu , Chenqi Jiang , Jingyao Huang , Haoran Wang , Di Wang , Chaoli Huang , Peng Jiang , Cunming Liu , Xiaolin Yang , Chun Yang , Ling Yang , Riyue Jiang

Empathy plays a crucial role in social communication and the perception of affective states and behavioral processes. In this study, we observed that empathic interaction with a mouse experiencing pain resulted in decreased mechanical pain thresholds and anxiety-like behaviors in its bystander, though the underlying mechanisms remain unknown. We demonstrated that CD38 expression in the paraventricular nucleus (PVN) was upregulated during empathic pain, and the pain and emotions of CD38 knockout (CD38KO) mice as bystanders were not affected. Furthermore, fiber photometry recordings indicated that calcium activities of PVN neurons were increased during empathic pain. Interestingly, direct chemogenetic inhibition of PVN neurons attenuated the hyperalgesia and anxiety-like behaviors associated with empathic pain. In contrast, activating PVN neurons through chemogenetics in CD38KO mice induced hyperalgesia and anxiety-like effects in empathic pain. Oxytocin levels in PVN were upregulated during empathic pain, while CD38KO mice inhibit the upregulation in OXT levels, confirming that CD38 is involved in releasing brain OXT and that the CD38-OXT system in the PVN plays a role in empathic pain. Collectively, CD38-mediated oxytocin signaling in PVN is closely linked to empathic pain through its effect on the activation of PVN neurons, and it could be viable targets for novel empathic behavior interventions.

共情在社会交际、情感状态感知和行为过程中起着至关重要的作用。在本研究中，我们观察到与经历疼痛的小鼠的共情互动导致其旁观者的机械疼痛阈值和焦虑样行为降低，尽管潜在的机制尚不清楚。我们证明，在共情疼痛期间，室旁核（PVN）中的CD38表达上调，而CD38敲除（CD38KO）小鼠作为旁观者的疼痛和情绪不受影响。此外，纤维光度记录显示，在共情疼痛时PVN神经元的钙活性增加。有趣的是，PVN神经元的直接化学发生抑制减轻了与共情疼痛相关的痛觉过敏和焦虑样行为。相比之下，通过化学遗传学激活CD38KO小鼠的PVN神经元可诱导共情疼痛的痛觉过敏和焦虑样效应。共情疼痛时，PVN内催产素水平上调，而CD38KO小鼠抑制OXT水平上调，证实CD38参与脑OXT的释放，PVN内CD38-OXT系统在共情疼痛中发挥作用。综上所述，cd38介导的PVN催产素信号通过其对PVN神经元激活的影响与共情疼痛密切相关，它可能是新型共情行为干预的可行靶点。

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引用次数: 0

Effects of chronic ethanol exposure on dorsal medial striatal neurons receiving convergent inputs from the orbitofrontal cortex and basolateral amygdala 慢性乙醇暴露对接受眶额皮质和杏仁核基底外侧趋同输入的背内侧纹状体神经元的影响。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-13 DOI: 10.1016/j.neuropharm.2025.110303

Sudarat Nimitvilai-Roberts , Marcelo F. Lopez , John J. Woodward

Alcohol use disorder is associated with altered function of cortical-amygdala-striatal circuits such as the orbitofrontal cortex (OFC), basolateral amygdala (BLA) and their connections to the dorsal medial striatum (DMS) shown to be involved in goal-directed actions. Using retrobead tracing, we previously reported enhanced excitability of DMS-projecting OFC neurons in mice following 3-to-7-day withdrawal from chronic intermittent ethanol (CIE) exposure. In the same animals, spiking of DMS-projecting BLA neurons was decreased at 3-days post-withdrawal followed by an increase in firing at 7- and 14-days. In the current study, we used transsynaptic labeling and slice electrophysiology to investigate the effects of CIE exposure on DMS neurons that receive convergent inputs from the OFC and BLA. Mice were infused with anterograde transsynaptic AAVs in the OFC (AAV1-Cre) and BLA (AAV1-Flpo) and a Cre-On/Flp-On-YFP AAV in the DMS followed by 4 weekly cycles of Air or CIE vapor exposure. Current-clamp recordings of YFP + DMS^OFC−BLA neurons showed three distinct patterns of firing: regular spiking, regular spiking followed by depolarization block and regular spiking with the appearance of broadened action potentials and plateau potentials at higher current steps (termed FANS). In both male and female mice, withdrawal from CIE exposure significantly increased the excitability of regular spiking neurons as compared to air controls. More subtle effects were observed on FANS neurons with both increases and decreases in firing that were current step and sex-dependent. These findings add to a growing literature demonstrating how neurons within cortical-amygdala-striatal circuits implicated in compulsive/habitual behaviors are impacted by chronic alcohol exposure.

酒精使用障碍与皮质-杏仁核-纹状体回路的功能改变有关，如眶额皮质（OFC）、基底外侧杏仁核（BLA）及其与背内侧纹状体（DMS）的连接被证明与目标导向行为有关。通过反向追踪，我们之前报道了在慢性间歇乙醇（CIE）暴露3- 7天后小鼠dms -投射OFC神经元的兴奋性增强。在同样的动物中，dms -突出的BLA神经元的尖峰在停药后3天减少，随后在7天和14天增加。在当前的研究中，我们使用跨突触标记和切片电生理学来研究CIE暴露对接收OFC和BLA收敛输入的DMS神经元的影响。小鼠OFC （AAV1-Cre）和BLA （AAV1-Flpo）中注入顺行跨突触AAV， DMS中注入Cre-On/Flp-On-YFP AAV，然后进行4周的空气或CIE蒸汽暴露。YFP + DMSOFC-BLA神经元的电流钳记录显示三种不同的放电模式：有规律的尖峰，有规律的尖峰后去极化阻滞，有规律的尖峰，在高电流阶（称为FANS）出现动作电位和平台电位的加宽。在雄性和雌性小鼠中，与空气控制相比，从CIE暴露中退出显着增加了常规尖峰神经元的兴奋性。在fan神经元上观察到更微妙的影响，放电的增加和减少是当前步骤和性别依赖的。这些发现为越来越多的文献提供了证据，证明与强迫/习惯性行为有关的皮质-杏仁核-纹状体回路中的神经元如何受到慢性酒精暴露的影响。

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引用次数: 0

Berberine ameliorates seizure activity and cardiac dysfunction in pentylenetetrazol-kindling seizures in rats: Modulation of sigma1 receptor, Akt/eNOS signaling, and ferroptosis 小檗碱改善戊四唑点燃大鼠癫痫发作的癫痫活动和心功能障碍：调节sigma1受体、Akt/eNOS信号和铁下垂。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-10 DOI: 10.1016/j.neuropharm.2025.110295

Shrouk M. Basiouny , Hala F. Zaki , Shimaa M. Elshazly , Ahmed F. Mohamed

Seizures can lead to cardiac dysfunction. Multiple pathways contribute to this phenomenon, of which the chaperone sigma-1 receptor (S1R) signaling represents a promising nexus between the abnormalities seen in both epilepsy and ensuing cardiac complications. The study explored the potential of Berberine (BER), a promising S1R agonist, in treating epilepsy and associated cardiac abnormalities in a pentylenetetrazol (PTZ) kindling rat model of epilepsy. Male Wistar albino rats received PTZ (35 mg/kg) every other day alone, with BER, with phenytoin (PHT), with both BER and PHT and with both BER and an S1R blocker (NE-100) over 27 days. BER decreased seizure severity and improved hemodynamic parameters. Histopathological abnormalities were more pronounced in the PTZ, and blocker group than in other groups, in heart tissue. In cardiac tissue, BER enhanced the AKT/eNOS signaling pathway and mitigated ferroptosis by boosting the cystine/glutamate transporter/Glutathione/Glutathione Peroxidase 4 (XCT/GSH/GPX4) system and ferritin heavy chain-1 (FTH-1) expression, while reducing iron and Transferrin receptor protein 1 (TFR1) levels. Such effects were largely negated by NE-100 pretreatment. In conclusion, BER shows protective effects on cardiac dysfunction induced by the PTZ kindling model by acting as an S1R agonist and influencing the AKT/eNOS signaling pathway and ferroptosis.

癫痫会导致心功能障碍。多种途径促成了这一现象，其中伴侣-1受体（S1R）信号代表了癫痫和随后的心脏并发症之间异常的有希望的联系。本研究探讨了一种有前景的S1R激动剂小檗碱（Berberine， BER）在戊四氮唑（PTZ）点燃大鼠癫痫模型中治疗癫痫和相关心脏异常的潜力。雄性Wistar白化大鼠每隔一天单独给予PTZ (35 mg/kg)，联合BER、苯妥英（PHT）、BER和PHT以及BER和S1R阻滞剂（NE-100），持续27天。BER降低了癫痫发作的严重程度，改善了血流动力学参数。在心脏组织中，PTZ和阻滞剂组的组织病理学异常比其他组更为明显。在心脏组织中，BER通过提高胱氨酸/谷氨酸转运体/谷胱甘肽/谷胱甘肽过氧化物酶4 （XCT/GSH/GPX4）系统和铁蛋白重链-1 （FTH-1）的表达，同时降低铁和转铁蛋白受体蛋白1 （TFR1）的水平，增强AKT/eNOS信号通路，减轻铁凋亡。经NE-100预处理后，这些作用在很大程度上被抵消。综上所述，BER通过作为S1R激动剂，影响AKT/eNOS信号通路和铁凋亡，对PTZ点燃模型引起的心功能障碍具有保护作用。

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引用次数: 0

The novel miR_146-Tfdp2 axis antagonizes METH induced neuron apoptosis and cell cycle abnormalities in tree shrew 新型miR_146-Tfdp2轴拮抗甲基醚诱导的树鼩神经元凋亡和细胞周期异常。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-09 DOI: 10.1016/j.neuropharm.2025.110300

Shuwei Zhang , Chan Wang , Jianxing Liu , Liu Liu , Lin Miao , Haowei Wang , Yunqing Tian , Hao Cheng , Juan Li , Xiaofeng Zeng

Methamphetamine (METH) is a synthetic drug with potent addictive, relapse, and neurotoxic properties. METH abuse contributes to severe damage to the central nervous system, potentially causing cognitive impairments, behavioral changes, and neurodegenerative diseases. METH-induced neuronal damage is closely related to apoptosis and cell cycle abnormalities, while gene expression regulator microRNAs (miRNAs) may play extensive roles in this progress, but the specific mechanisms remain unclear. We found that the novel miRNA 146 (miR_146) was downregulated in METH-induced apoptosis and cell cycle arrest in tree shrew primary neurons, while the expression of its target gene Tfdp2 was increased after METH exposure. Overexpression of miR_146 or silencing of Tfdp2 significantly alleviated METH-induced cell cycle arrest and apoptosis in primary tree shrew neurons. These findings provide new insights into the role of the miR_146-Tfdp2 axis in METH-induced neurotoxic injury and offer a theoretical basis for miR_146 as potential therapeutic targets in drug abuse.

甲基苯丙胺（冰毒）是一种合成药物，具有强烈的成瘾性、复发性和神经毒性。滥用冰毒会对中枢神经系统造成严重损害，可能导致认知障碍、行为改变和神经退行性疾病。meth诱导的神经元损伤与细胞凋亡和细胞周期异常密切相关，而基因表达调控因子microRNAs （miRNAs）可能在这一过程中发挥了广泛的作用，但具体机制尚不清楚。我们发现，在冰毒诱导的树鼩原代神经元凋亡和细胞周期阻滞中，新型miRNA 146 （miR_146）表达下调，而其靶基因Tfdp2在冰毒暴露后表达升高。miR_146过表达或Tfdp2沉默可显著减轻甲基醚诱导的树鼩原代神经元细胞周期阻滞和凋亡。这些发现为miR_146- tfdp2轴在甲基甲醚诱导的神经毒性损伤中的作用提供了新的见解，并为miR_146作为药物滥用的潜在治疗靶点提供了理论基础。

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引用次数: 0

Female Syrian hamster analyses of bremelanotide, a US FDA approved drug for the treatment of female hypoactive sexual desire disorder 雌性叙利亚仓鼠对bremelanotide的分析，bremelanotide是一种美国FDA批准用于治疗女性性欲减退障碍的药物。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-09 DOI: 10.1016/j.neuropharm.2025.110299

Johnathan M. Borland , Abigail L. Kohut-Jackson , Anna C. Peyla , Megan AL. Hall , Paul G. Mermelstein , Robert L. Meisel

Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions.

性欲减退（HSDD）是世界范围内报道最多的绝经前妇女性功能障碍。Bremelanotide，商品名Vyleesi，已被美国食品和药物管理局批准用于治疗HSDD。然而，尽管获得批准，但对其作用的神经生物学机制知之甚少。在这项研究中，我们利用雌性叙利亚仓鼠模型来研究bremelanotide对中脑边缘多巴胺系统黑素皮质素受体表达和性奖励的影响。我们发现大部分黑素皮质素3和4 （MC4R）受体mRNA在腹侧被盖区（VTA）的多巴胺神经元中表达。在伏隔核（NAc）或背纹状体中表达MC4R的神经元较少，它们很少与表达多巴胺D1或D2受体的神经元共定位。相反，MC4R mRNA在伏隔核中间神经元中表达。低剂量和高剂量对中脑边缘多巴胺系统黑素皮质素受体mRNA的表达均无影响。最后，性经验导致雌性叙利亚仓鼠的条件位置偏好（CPP），尽管在本试验中，布雷梅莱诺肽治疗未能提高性奖励。本研究的结果与在大鼠身上进行的类似研究相结合，得出的结论是，bremelanotide不作用于VTA-NAc奖励回路，也不会增强性互动的奖励效果。

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引用次数: 0

Baicalin ameliorates neuroinflammation by targeting TLR4/MD2 complex on microglia via PI3K/AKT/NF-κB signaling pathway 黄芩苷通过PI3K/AKT/NF-κB信号通路靶向小胶质细胞上的TLR4/MD2复合物，改善神经炎症。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-09 DOI: 10.1016/j.neuropharm.2025.110296

Yufang Lu , Ruiying Zhou , Ruyi Zhu , Xue Wu , Jin Liu , Yue Ma , Xin Zhang , Yaling Zhang , Luting Yang , Yanhua Li , Yuan Zhang , Yaping Yan , Qian Zhang

This study aims to elucidate the target and mechanism of baicalin, a clinically utilized drug, in the treatment of neuroinflammatory diseases. Neuroinflammation, characterized by the activation of glial cells and the release of various pro-inflammatory cytokines, plays a critical role in the pathogenesis of various diseases, including spinal cord injury (SCI). The remission of such diseases is significantly dependent on the improvement of inflammatory microenvironment. Toll-like receptor 4/myeloid differentiation protein 2 (TLR4/MD2) complex plays an important role in pathogen recognition and innate immune activation. baicalin, a natural flavonoid, is renowned for its potent anti-inflammatory property. In this study, we discovered that baicalin significantly reduced the activation of glial cells and the levels of pro-inflammatory cytokines at the lesion site of SCI mice, thereby mitigating demyelination and neuronal damage. By directly occupying the active pocket of TLR4/MD2 complex on microglia, baicalin inhibited PI3K/AKT/NF-κB pathway, thereby exerting its anti-inflammatory effect. These findings were corroborated in mice induced by lipopolysaccharide, a TLR4 agonist. Furthermore, baicalin indirectly altered phenotype of astrocytes by reducing secretion of TNF-α, IL-1α, and C1q levels from microglia. Our work demonstrated that baicalin effectively alleviated neuroinflammation by directly targeting microglia and indirectly modulating astrocytes phenotype. As a natural flavonoid, baicalin holds significant potential as a therapeutic candidate for diseases characterized by neuroinflammation.

本研究旨在阐明临床常用药物黄芩苷治疗神经炎性疾病的作用靶点及作用机制。神经炎症以神经胶质细胞的激活和各种促炎细胞因子的释放为特征，在包括脊髓损伤（SCI）在内的多种疾病的发病机制中起着关键作用。这些疾病的缓解明显依赖于炎症微环境的改善。toll样受体4/髓样分化蛋白2 （TLR4/MD2）复合物在病原体识别和先天免疫激活中起重要作用。黄芩苷是一种天然类黄酮，以其有效的抗炎特性而闻名。在本研究中，我们发现黄芩苷可以显著降低脊髓损伤小鼠损伤部位的胶质细胞活化和促炎细胞因子水平，从而减轻脱髓鞘和神经元损伤。黄芩苷通过直接占据小胶质细胞上TLR4/MD2复合物的活性口袋，抑制PI3K/AKT/NF-κB通路，从而发挥其抗炎作用。这些发现在TLR4激动剂脂多糖诱导的小鼠中得到证实。此外，黄芩苷通过降低小胶质细胞分泌TNF-α、IL-1α和C1q水平间接改变星形胶质细胞的表型。我们的研究表明黄芩苷通过直接靶向小胶质细胞，间接调节星形胶质细胞表型，有效减轻神经炎症。作为一种天然类黄酮，黄芩苷作为一种以神经炎症为特征的疾病的治疗候选物具有重要的潜力。

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引用次数: 0

The effects of social loss and isolation on partner odor investigation and dopamine and oxytocin receptor expression in female prairie voles 社会丧失和孤立对草原田鼠配偶气味调查及多巴胺和催产素受体表达的影响。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-06 DOI: 10.1016/j.neuropharm.2025.110298

Adrianna Kirckof , Emma Kneller , Erika M. Vitale , Michael A. Johnson , Adam S. Smith

In humans, grief is characterized by intense sadness, intrusive thoughts of the deceased, and intense longing for reunion with the deceased. Human fMRI studies show hyperactivity in emotional pain and motivational centers of the brain when an individual is reminded of a deceased attachment figure, but the molecular underpinnings of these changes in activity are unknown. Prairie voles (Microtus ochrogaster), which establish lifelong social bonds between breeding pairs, also display distress and motivational shifts during periods of prolonged social loss, providing a model to investigate these behavioral and molecular changes at a mechanistic level. Here, a novel odor preference test was used to assess social vs non-social odor investigation, and a sucrose preference test was used to assess non-social, reward-driven motivation. Females that lost a male partner investigated partner- and food-associated cues significantly more than females that lost a female cagemate or remained intact with a male partner. However, females experiencing the loss of a male partner did not change investigation of stranger-associated cues. Western blotting revealed significant increases of dopamine receptor type 1 (DRD1) and oxytocin receptor protein content in specific brain regions in response to the loss of distinct social relationships. Such effects included an increase in DRD1 in the medial preoptic area of the hypothalamus (mPOA) in females experiencing loss of a male partner compared to all other conditions. Pharmacological antagonism of DRD1 in the mPOA blocked the loss-associated increase of investigation of the partner odor but did not affect investigation of food or stranger odors. This reveals a novel dopamine-mediated mechanism for partner-seeking behavior during periods of partner loss in female prairie voles.

在人类中，悲伤的特征是强烈的悲伤，对死者的侵入性思想，以及对与死者团聚的强烈渴望。人类功能磁共振成像研究显示，当一个人想起已故的依恋对象时，情绪痛苦和大脑的动机中心会异常活跃，但这些活动变化的分子基础尚不清楚。草原田鼠（Microtus ochrogaster）在繁殖对之间建立了终生的社会关系，在长期的社会损失期间也会表现出痛苦和动机转变，这为在机制水平上研究这些行为和分子变化提供了一个模型。本研究采用一种新的气味偏好测试来评估社会性和非社会性气味调查，并采用蔗糖偏好测试来评估非社会性、奖励驱动的动机。失去雄性伴侣的雌性比失去雌性或与雄性伴侣保持完整关系的雌性更容易调查与伴侣和食物有关的线索。然而，失去男性伴侣的女性并没有改变对陌生人相关线索的调查。Western blotting显示，在特定的大脑区域，多巴胺受体1型（DRD1）和催产素受体蛋白含量显著增加，这是对特定社会关系丧失的反应。这些影响包括与其他情况相比，在失去男性伴侣的女性中，下丘脑内侧视前区（mPOA）的DRD1增加。mPOA中DRD1的药理拮抗作用阻断了对伴侣气味调查的损失相关增加，但不影响对食物或陌生人气味的调查。这揭示了一种多巴胺介导的雌性草原田鼠在失去伴侣期间寻找伴侣行为的新机制。

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引用次数: 0

Leveling up: Strategies for taking Neuropharmacology and us all to new heights 升级：将神经药理学和我们所有人带到新高度的策略。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-06 DOI: 10.1016/j.neuropharm.2025.110297

Jared W. Young Ph.D

引用次数: 0

Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells 胆固醇代谢物调节小胶质细胞中P2X4和P2X7受体电流。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-01-02 DOI: 10.1016/j.neuropharm.2024.110294

Michele Barraco , Eva Kudova , Claudio Bucolo , Lucia Ciranna , Maria Angela Sortino , Mariangela Chisari

The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It is well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic and NMDA glutamatergic receptors in neurons. It has been shown that also ionotropic purinergic (P2X) receptors are cholesterol metabolites’ targets. Among P2X receptors, purinergic P2X4 and P2X7 receptors are expressed in microglia, the innate immune cells involved in the brain inflammatory response. In this study, we explore the ionotropic purinergic receptors modulation by cholesterol metabolites in microglia. Patch-clamp experiments were performed in BV2 cells, a murine microglia cell line, to evaluate effects of cholesterol metabolites using micro- and nanomolar concentrations. About P2X4 receptor, we found that testosterone butyrate (20 μM and 200 nM) and allopregnanolone (10 μM and 100 nM) both potentiated its current, while neither 25-hydroxycholesterol (10 μM and 100 nM) nor 17β-estradiol (1 μM) showed any effects. On the other hand, P2X7 receptor current was potentiated by allopregnanolone (10 μM) and 25-hydroxycholesterol (10 μM and 100 nM). Taken together, our data show that modulation of either P2X4 and P2X7 current is affected differently by cholesterol metabolites, suggesting a structure-activity relationship among these players. Identifying the possible link between purinergic transmission, microglia and cholesterol metabolites will allow to define new targets for drug development to treat neuroinflammation.

中枢神经系统是众所周知的类固醇生成组织，产生胆固醇代谢产物，如神经活性类固醇、羟甾醇和类固醇激素。众所周知，这些内源性分子影响几种受体，包括神经元中的嗜离子性gaba能受体和NMDA谷氨酸能受体。研究表明，嗜离子嘌呤能（P2X）受体也是胆固醇代谢产物的靶点。在P2X受体中，嘌呤能P2X4和P2X7受体在参与脑炎症反应的先天免疫细胞小胶质细胞中表达。在本研究中，我们探讨了小胶质细胞中胆固醇代谢产物对嗜离子嘌呤能受体的调节。膜片钳实验在小鼠小胶质细胞BV2细胞中进行，以评估微摩尔浓度和纳摩尔浓度对胆固醇代谢物的影响。对于P2X4受体，我们发现丁酸睾酮（20 μM和200 nM）和异孕酮（10 μM和100 nM）均能增强其电流，而25-羟基胆固醇（10 μM和100 nM）和17β-雌二醇（1 μM）对其电流没有影响。另一方面，异孕酮（10 μM）和25-羟基胆固醇（10 μM和100 nM）可增强P2X7受体电流。综上所述，我们的数据显示P2X4和P2X7电流的调节受到胆固醇代谢物的不同影响，表明这些参与者之间存在结构-活性关系。确定嘌呤能传递、小胶质细胞和胆固醇代谢物之间的可能联系，将有助于确定治疗神经炎症的药物开发的新目标。

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