Neuropharmacology最新文献_第2页

Spinal Shati/nat8l regulates mechanical hyperalgesia through NAAG-mGluR3 signaling in neuropathic pain 脊髓沙/ nat81通过NAAG-mGluR3信号调控神经性疼痛的机械性痛觉过敏。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-31 DOI: 10.1016/j.neuropharm.2025.110819

Keisuke Miyamoto , Kousuke Tatsuta , Kazuyuki Sumi , Kyosuke Uno , Kazuki Tokoro , Shin-ichi Muramatsu , Naotaka Izuo , Kazuhiko Kume , Atsumi Nitta , Masahiro Ohsawa

Shati/nat8l catalyzes the synthesis of N-acetylaspartate (NAA), a precursor for N-acetylaspartylglutamate (NAAG), an endogenous agonist of group II metabotropic glutamate receptor 3 (mGluR3). Although spinal mGluR3 is known to modulate nociceptive signaling, the functional role of Shati/nat8l in pain transmission has remained unclear. In this study, we investigated the involvement of spinal Shati/nat8l in mechanical nociceptive processing and neuropathic pain.

We found that Shati/nat8l knockout (Shati−/−) mice exhibited a significantly decreased mechanical pain threshold compared to wild-type controls. This hypersensitivity was reversed by adeno-associated virus (AAV)-mediated expression of Shati/nat8l in the spinal dorsal horn. Intrathecal administration of NAAG—but not NAA—restored mechanical thresholds in Shati−/− mice, and this effect was blocked by the group II mGluR antagonist LY341495. In addition, treatment with LY341495 showed antinociceptive effect in normal mice at higher doses. In a peripheral nerve injury model, expression of Shati/nat8l mRNA in the ipsilateral dorsal horn was significantly decreased. Importantly, AAV-mediated restoration of Shati/nat8l expression in the dorsal horn alleviated neuropathic mechanical hyperalgesia and normalized Shati/nat8l mRNA levels.

These findings suggest that downregulation of spinal Shati/nat8l contributes to mechanical hypersensitivity by impairing the NAAG-mGluR3 signaling pathway. Targeting the Shati/nat8l–NAAG–mGluR3 axis may offer a novel therapeutic strategy for the treatment of neuropathic pain.

Shati/nat8l可催化n -乙酰天冬氨酸（NAA）的合成，NAA是n -乙酰天冬氨酸谷氨酸（NAAG）的前体，NAAG是II组代谢型谷氨酸受体3 （mGluR3）的内源性激动剂。虽然已知脊髓mGluR3可以调节伤害性信号，但Shati/ nat81在疼痛传递中的功能作用仍不清楚。在这项研究中，我们研究了脊髓沙/ nat81在机械性伤害知觉加工和神经性疼痛中的参与。我们发现，与野生型对照相比，Shati/nat8l基因敲除（Shati-/-）小鼠的机械痛阈值显著降低。这种超敏反应被腺相关病毒（AAV）介导的脊髓背角Shati/ nat81的表达逆转。鞘内给药naag（而非naag）恢复了Shati-/-小鼠的机械阈值，这种作用被II组mGluR拮抗剂LY341495阻断。此外，LY341495在高剂量下对正常小鼠具有抗伤害感受性作用。在周围神经损伤模型中，同侧背角Shati/ nat81mrna的表达明显降低。重要的是，aav介导的背角Shati/nat8l表达的恢复减轻了神经性机械性痛觉过敏，并使Shati/nat8l mRNA水平正常化。这些发现表明，脊柱Shati/nat8l的下调通过损害NAAG-mGluR3信号通路参与机械超敏反应。靶向Shati/nat8l-NAAG-mGluR3轴可能为神经性疼痛的治疗提供一种新的治疗策略。

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引用次数: 0

TRPC6 mediates neuronal hyperexcitability in the lateral habenula to drive trigeminal neuralgia-associated anxiety TRPC6介导外侧缰神经高兴奋性驱动三叉神经痛相关焦虑

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-30 DOI: 10.1016/j.neuropharm.2025.110818

Fengxian Hu , Zhenling Liu , Xiaoman Min , Kaixin Zhang , Hengye Zhao , Wei Liu , Yi Tao , Qingyue Jia , Yaqing Gao , Xianrui Meng , Yu Wang , Hongyun Wu , Wenqiang Cui

Persistent facial and oral discomfort, particularly trigeminal neuralgia (TN), is frequently accompanied by anxiety, which has been closely linked to increased excitability of neurons in the lateral habenula (LHb). However, the mechanisms underlying this hyperexcitability remain unclear. Here, we show that partial transection of the infraorbital nerve (pT-ION) significantly upregulated the expression of transient receptor potential canonical 6 (TRPC6), β isoform of calcium/calmodulin-dependent protein kinase II (βCaMKII), phosphorylated extracellular regulated kinase (p-ERK), and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in the LHb. Pharmacological blockade of either TRPC6 or βCaMKII effectively reversed pT-ION-induced mechanical hypersensitivity and anxiety-like behaviors. TRPC6 overexpression in the LHb reproduced the behavioral and electrophysiological phenotypes observed in pT-ION mice, including increased LHb neuronal excitability. In contrast, bilateral knockdown of TRPC6 attenuated both pain- and anxiety-like behaviors and normalized neuronal activity in the LHb. Our study identified TRPC6 as a key mediator of LHb neuronal hyperexcitability, contributing to trigeminal neuralgia-associated pain and anxiety via the βCaMKII/ERK/CREB pathway, and suggests its potential as a target for treatment.

持续的面部和口腔不适，特别是三叉神经痛（TN），经常伴有焦虑，这与外侧缰（LHb）神经元兴奋性增加密切相关。然而，这种超兴奋性的机制尚不清楚。在这里，我们发现眶下神经的部分横断（pT-ION）显著上调了LHb中瞬时受体电位规范6 （TRPC6）、钙/钙调素依赖性蛋白激酶II （β camkii）的β亚型、磷酸化的细胞外调节激酶（p-ERK）和磷酸化的环腺苷单磷酸反应元件结合蛋白（p-CREB）的表达。药物阻断TRPC6或βCaMKII均可有效逆转pt - ion诱导的机械超敏反应和焦虑样行为。TRPC6在LHb中的过表达再现了在pT-ION小鼠中观察到的行为和电生理表型，包括LHb神经元兴奋性增加。相比之下，双侧TRPC6的敲低减轻了LHb的疼痛和焦虑样行为以及正常化的神经元活动。我们的研究发现TRPC6是LHb神经元高兴奋性的关键介质，通过βCaMKII/ERK/CREB通路促进三叉神经痛相关的疼痛和焦虑，并提示其作为治疗靶点的潜力。

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引用次数: 0

Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and A2a receptor-expressing medium spiny neurons in nucleus accumbens core and shell 羟考酮渴求的潜伏期与表达D1和A2a受体的伏隔核和壳中棘神经元中CP-AMPAR的上调有关。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-26 DOI: 10.1016/j.neuropharm.2025.110816

Kimberley A. Mount , Hayley M. Kuhn, Eun-Kyung Hwang, Madelyn M. Beutler, Marina E. Wolf

A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naïve animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions after forced abstinence from extended-access oxycodone or saline self-administration, using male and female wild-type and transgenic rats. Before incubation (abstinence days 1–2), CP-AMPAR upregulation was not detected in either D1 or A2a (D2) receptor-expressing MSN. After incubation had stably plateaued (abstinence days 17–33), CP-AMPARs were elevated in both MSN subtypes in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell prevents expression of oxycodone incubation. However, CP-AMPAR upregulation on both MSN subtypes contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity.

治疗阿片类药物使用障碍的一个主要问题是长期戒断后的持续渴望。这已经在啮齿类动物身上用渴望的潜伏期模型进行了模拟，在这种模型中，线索诱导的药物寻求在自我戒断药物的第一周增加，然后在较长一段时间内保持高水平。包括羟考酮在内的几种阿片类药物的潜伏期已被报道，但对潜在的突触可塑性知之甚少。相反，可卡因和甲基苯丙胺渴望的培养依赖于伏隔核（NAc）中谷氨酸突触通过钙渗透AMPARs （CP-AMPARs）的结合而增强。在drug-naïve动物中，CP-AMPARs比钙不渗透性AMPARs具有更高的电导率，并具有其他独特的特性。本研究以雄性和雌性野生型和转基因大鼠为研究对象，研究了在强制戒断可酮或生理盐水后，NAc核和壳区中棘神经元（MSN）中AMPAR的传递。在孵育前（禁食1-2天），在表达D1或A2a （D2）受体的MSN中均未检测到CP-AMPAR上调。在孵育达到稳定的平台期（禁食17-33天）后，两个亚区两种MSN亚型的cp - ampar均升高。这些结果解释了先前的研究表明，将选择性CP-AMPAR拮抗剂注入NAc核或壳中可阻止氧可酮孵育的表达。然而，CP-AMPAR对两种MSN亚型的上调与可卡因和甲基苯丙胺培养后D1 MSN的选择性上调形成对比。我们的研究结果表明，尽管在MSN亚型特异性上存在差异，但CP-AMPAR上调在精神兴奋剂和羟考酮培养中具有共同作用。

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引用次数: 0

Cell models to probe the biological bases of antipsychotic-induced metabolic Syndrome: towards an individual specific approach 细胞模型探索抗精神病诱导代谢综合征的生物学基础：迈向个体特异性途径

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-24 DOI: 10.1016/j.neuropharm.2025.110814

Maria Fiore , Silvia Saltarelli , Laura De Mastro , Enrico D'Ambrosio , Antonia Ianniello , Alessandro Bertolino , Giulio Pergola , Maria Favia , Antonio Rampino

Background

Individuals with major psychiatric disorders are at an increased risk of developing Metabolic Syndrome (MetS), partly attributed to the dysmetabolic side effects of Second-Generation Antipsychotics (SGAs). In vitro cell models of peripheral tissues provide a valid platform to investigate the biochemical and molecular alterations induced by SGAs at the peripheral level in conjunction with their effects on the central nervous system. This scoping review summarizes two decades of studies utilizing established cell lines and primary rodent cells to examine the direct dysmetabolic effects of antipsychotics (APs) on lipid and glucose metabolism, inflammatory pathways, and mitochondrial function.

Methods

We identified published scientific literature in the PubMed database using the following search strategy: (“antipsychotic” OR “olanzapine” OR “clozapine” OR “risperidone” OR “quetiapine” OR “haloperidol”) AND (“metabolic syndrome” OR “insulin action” OR “insulin resistance” OR “up-regulation” OR “down-regulation” OR “dyslipidemia”) AND (cell models).

Results

Out of 121 articles identified, 21 met the eligibility criteria and were included in the review, with their methods and findings organized according to the AP-affected biological processes implicated in MetS.

Conclusions

Independent studies on cell models confirm the AP-pathogenic role on gene and protein expression regulation involved in lipid and glucose metabolism, inflammatory processes, and impairments at the mitochondrial level.

In the final section of the manuscript, we highlight the potential of individual-specific stem-cell–based models, like induced pluripotent stem cells, to investigate gene-by-medication interactions relevant to AP-induced MetS. However, these stem-cell approaches fall outside the scope of the present review and were not included in our literature search.

背景：患有严重精神疾病的个体发生代谢综合征（MetS）的风险增加，部分原因是第二代抗精神病药物（SGAs）的代谢不良副作用。体外外周组织细胞模型为研究SGAs在外周水平诱导的生化和分子改变及其对中枢神经系统的影响提供了一个有效的平台。本综述总结了二十年来利用已建立的细胞系和原代啮齿动物细胞来研究抗精神病药物（APs）对脂质和葡萄糖代谢、炎症途径和线粒体功能的直接代谢不良影响的研究。方法我们使用以下搜索策略在PubMed数据库中识别已发表的科学文献：（抗精神病药）或“奥氮平”或“氯氮平”或“利培酮”或“喹硫平”或“氟哌啶醇”)和（代谢综合征”或“胰岛素作用”或“胰岛素抵抗”或“上调”或“下调”或“血脂异常”）和（细胞模型）。结果在121篇文章中，21篇符合入选标准，纳入了本综述，他们的方法和发现是根据与MetS相关的ap影响的生物学过程组织的。对细胞模型的独立研究证实了ap在脂质和糖代谢、炎症过程和线粒体水平损伤的基因和蛋白质表达调控中的致病作用。在论文的最后部分，我们强调了基于个体特异性干细胞模型的潜力，如诱导多能干细胞，研究与ap诱导的MetS相关的基因-药物相互作用。然而，这些干细胞方法不在本综述的范围之内，也没有包括在我们的文献检索中。

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引用次数: 0

Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility 短RFamide， CFamide和FCamide肽作为ASIC 3的新阳性调节剂，具有相似的增强作用，但可逆性不同。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110813

Maurizio Toft , Maëva Meynier , Hélène Lubrano Di Scampamorte , Cédric Vallée , Miguel Salinas , Peijun Zhang , Jessica Tacco , Anne-Sophie Gay , Emmanuel Bourinet , Eric Lingueglia , Emmanuel Deval

Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR

\overline{CC}

RFamide) and a CFamide peptide (FR

\overline{CRC}

Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR

\overline{CC}

RFamide peptide was much slower than those of FR

\overline{CRC}

Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR

\overline{CC}

RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.

酸敏感离子通道（asic）是DEG/ENaC家族的成员，包括唯一已知的肽门控离子通道。虽然asic是由质子门控的，但它们也对肽敏感，并由软体动物FMRFamide和其他以RFamide基序结尾的哺乳动物神经肽调节。我们发现了一组合成的短修饰六肽，它们不仅以RFamide基序结尾，而且以CFamide和FCamide结尾，它们是ASIC3酸诱导活性的有效正向调节剂。我们重点研究了其中的两个，RFamide肽（FR RFamide）和CFamide肽（FR Famide），证明它们对ASIC3具有相似的特异性和作用。这两种多肽的增强作用是由于对脱敏作用的强烈减缓，导致酸性pH（≤pH6.6）诱导的电流量增加，表观亲和范围为1 ~ 5 μM。令人惊讶的是，FR RFamide肽的洗脱动力学比FR Famide和其他已知的RFamide肽慢得多，这表明它们的作用机制可能存在差异。计算模型和结构-功能分析揭示了这两种肽与ASIC3的非质子结合位点的相互作用，正如之前报道的其他RFamide肽一样，但我们的数据还表明FR RFamide可能直接或间接涉及质子结合域的其他作用。这些发现扩大了我们对肽对asic的调节的理解，鉴定了新的ASIC3短调节因子，包括具有新的CFamide和FCamide结尾基序的肽，并使用它们的冲刷动力学作为新参数显示了这些肽之间的差异。

{"title":"Short RFamide, CFamide and FCamide peptides as novel positive modulators of ASIC3 with similar potentiating effects but different reversibility","authors":"Maurizio Toft , Maëva Meynier , Hélène Lubrano Di Scampamorte , Cédric Vallée , Miguel Salinas , Peijun Zhang , Jessica Tacco , Anne-Sophie Gay , Emmanuel Bourinet , Eric Lingueglia , Emmanuel Deval","doi":"10.1016/j.neuropharm.2025.110813","DOIUrl":"10.1016/j.neuropharm.2025.110813","url":null,"abstract":"<div><div>Acid-sensing ion channels (ASICs) are members of the DEG/ENaC family that includes the only known peptide-gated ion channels. While ASICs are gated by protons, they are also sensitive to peptides and are modulated by the molluscan FMRFamide and other mammalian neuropeptides ending by the RFamide motif. We identified a set of synthetic short amidated hexapeptides, which not only end by the RFamide motif but also by CFamide and FCamide, as potent positive modulators of ASIC3 acid-induced activity. We focused on two of them, a RFamide peptide (FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide) and a CFamide peptide (FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide), demonstrating that they have similar specificity for and effects on ASIC3. The potentiating effects of the two peptides are due to a strong slow-down of desensitization, leading to an increase in the amount of current induced by acid pH (≤pH6.6), with apparent affinities ranging from 1 to 5 μM. Surprisingly, the washout kinetic of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide peptide was much slower than those of FR<span><math><mrow><mover><mtext>CRC</mtext><mo>‾</mo></mover></mrow></math></span>Famide and other known RFamide peptides, suggesting potential differences in their mechanisms of action. Computational modeling and structure-function analysis reveal interactions of both peptides with the non-proton binding site of ASIC3 as already reported before for other RFamide peptides, but our data also suggest possible additional effects of FR<span><math><mrow><mover><mtext>CC</mtext><mo>‾</mo></mover></mrow></math></span>RFamide involving directly or indirectly the proton binding domain. These findings expand our understanding of ASICs’ modulation by peptides, identifying novel short modulators of ASIC3, including peptides with new CFamide and FCamide ending motifs, and showing differences between these peptides using their washout kinetic as a new parameter.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"287 ","pages":"Article 110813"},"PeriodicalIF":4.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dorsal raphe serotonergic neurons facilitate arousal from sevoflurane anesthesia by heterogeneously modulating neuronal activity in the basolateral amygdala 背中叶5 -羟色胺能神经元通过异质调节杏仁核基底外侧的神经元活动促进七氟醚麻醉后的觉醒。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110815

Cen Yang , Yuting He , Min Cai , Sa Wang , Yuhao Wang , Miao Wang , Huaning Wang , Yanyan Sun , Jiannan Li

Background

Although the dorsal raphe nucleus (DRN) serotonergic neurons—which play a key role in consciousness—send dense projections to the basolateral amygdala (BLA), the electrophysiological mechanisms underlying their role in general anesthesia regulation remain elusive.

Methods

Fiber photometry was used to monitor DRN serotonergic activity changes in the BLA during sevoflurane anesthesia and arousal process. Optogenetics and neuropharmacology were taken advantage to study the effects and receptor mechanisms. Additionally, in vivo electrophysiology was applied to elucidate the neurophysiological mechanisms underlying DRN serotonergic modulating BLA during sevoflurane anesthesia and arousal process.

Results

DRN serotonergic afferents in the BLA exhibited decreased activity during sevoflurane anesthesia compared to wakefulness. Optogenetic activation of DRN serotonergic terminals in BLA accelerated arousal from sevoflurane anesthesia, as evidenced by electroencephalographic (EEG) signatures and behavioral recovery. Microinjection of 5-hydroxytryptamine (5-HT)1A receptors agonist (but not 5-HT2A or 5-HT2C agonists) into the BLA similarly promoted anesthetic emergence. Mechanistically, DRN serotonergic input inhibited GABAergic neurons while exciting glutamatergic neurons in the BLA, with these effects persisting across both wakefulness and anesthetic states.

Conclusions

Our findings establish a functional role for the DRN serotonergic-BLA neural pathway in promoting arousal from sevoflurane general anesthesia. These results provide novel mechanistic insights into the neural circuitry underlying consciousness recovery.

背景：虽然中隔背核（DRN）的5 -羟色胺能神经元（在意识中起关键作用）向基底外侧杏仁核（BLA）发送密集的投射，但其在全身麻醉调节中的作用的电生理机制尚不清楚。方法：采用纤维光度法监测七氟醚麻醉和觉醒过程中DRN - 5 -羟色胺能活性的变化。利用光遗传学和神经药理学研究其作用和受体机制。此外，体内电生理学应用于阐明在七氟醚麻醉和觉醒过程中DRN - 5 -羟色胺能调节BLA的神经生理机制。结果：与清醒时相比，七氟醚麻醉时BLA中DRN - 5 -羟色胺能事件的活性降低。脑电图和行为恢复证明，光遗传激活BLA中DRN - 5 -羟色胺能末端加速了七氟醚麻醉后的觉醒。微量注射5-羟色胺（5-HT）1A受体激动剂（但不是5-HT2A或5-HT2C激动剂）进入BLA同样促进麻醉出现。从机制上讲，DRN的5 -羟色胺能输入抑制gaba能神经元，同时刺激BLA中的谷氨酸能神经元，这些影响在清醒和麻醉状态下都持续存在。结论：我们的研究结果确定了DRN - 5 -羟色胺能- bla神经通路在促进七氟醚全身麻醉唤醒中的功能作用。这些结果为意识恢复背后的神经回路提供了新的机制见解。

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引用次数: 0

Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors tenneurin -4敲低扰乱多巴胺动力学并减弱甲基苯丙胺诱导的行为。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110817

Wenbing Chen , Jun Yokose , Naotaka Izuo , Yusuke Yano , Tomoya Kaigawa , Nobuyuki Kai , Chikako Kamiyoshihara , Noriaki Ohkawa , Yuki Shigetsura , Shin-ichi Muramatsu , Atsumi Nitta

Methamphetamine (METH) addiction is a major global public health issue with significant societal consequences. Dopamine (DA) plays a central role in the neurobiological mechanisms of METH addiction, particularly by reinforcing reward pathways and modulating neuronal plasticity. Teneurin-4 (TENM4), a type II transmembrane protein, is essential for neural development and for establishing precise synaptic connectivity. However, the specific role of TENM4 in the nucleus accumbens (NAc) during METH-induced reward remains unclear. Here, we found that repeated METH exposure selectively increased TENM4 protein expression in the nucleus accumbens (NAc), prompting us to investigate its function using an AAV-CRISPR-mediated knockdown (TENM4KD) targeted to the NAc in mice. TENM4KD significantly attenuated the development of METH-induced conditioned place preference, without altering METH-induced hyperlocomotion. This behavioral deficit was paralleled by blunted dopamine dynamics; fiber photometry revealed impaired predictive DA signals during conditioning, and microdialysis confirmed a reduction in both basal and METH-evoked DA levels. Mechanistically, this impairment was not due to damage to dopaminergic neurons themselves but was linked to a loss of local GABAergic neurons within the medial NAc and a compensatory upregulation of the dopamine transporter (DAT). These findings uncover a critical role for TENM4 in maintaining the integrity of local NAc circuits that govern reward learning. Thus, TENM4 emerges as a potential molecular target for therapeutic intervention, as manipulating its expression in the NAc disrupts local inhibitory signaling and reduces METH-induced addictive behaviors.

甲基苯丙胺（冰毒）成瘾是一个具有重大社会后果的重大全球公共卫生问题。多巴胺（DA）在甲基苯丙胺成瘾的神经生物学机制中起着核心作用，特别是通过加强奖赏通路和调节神经元可塑性。tenneurin -4 （TENM4）是一种II型跨膜蛋白，对神经发育和建立精确的突触连接至关重要。然而，在冰毒诱导的奖赏过程中，TENM4在伏核（NAc）中的具体作用尚不清楚。在这里，我们发现反复暴露于甲基安非他明选择性地增加了TENM4蛋白在伏隔核（NAc）中的表达，这促使我们使用aav - crispr介导的针对小鼠NAc的敲低（TENM4KD）来研究其功能。TENM4KD显著减弱了甲基醚诱导的条件位置偏好的发展，但没有改变甲基醚诱导的过度运动。这种行为缺陷与多巴胺动力减弱相平行；纤维光度法显示，在调节过程中，预测性DA信号受损，微透析证实，基础和甲基安非他明诱发的DA水平都有所降低。从机制上讲，这种损伤不是由于多巴胺能神经元本身的损伤，而是与内侧NAc内局部gaba能神经元的丧失和多巴胺转运体（DAT）的代偿上调有关。这些发现揭示了TENM4在维持控制奖励学习的局部NAc回路的完整性方面的关键作用。因此，TENM4成为治疗干预的潜在分子靶点，因为操纵其在NAc中的表达会破坏局部抑制信号并减少冰毒诱导的成瘾行为。

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引用次数: 0

Targeting treatment-resistant social anxiety with sitagliptin: Effects on social fear and comorbid depressive-like behavior in a preclinical model 西格列汀治疗难治性社交焦虑：临床前模型中对社交恐惧和共病抑郁样行为的影响

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-23 DOI: 10.1016/j.neuropharm.2025.110812

Iulia Zoicas, Johannes Kornhuber

Social anxiety disorder (SAD) is often complicated by comorbid depression and resistance to standard treatments, yet therapeutic strategies that effectively address both core and comorbid symptoms remain limited. We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor commonly used in the treatment of type 2 diabetes mellitus, effectively reduces social fear in mice subjected to social fear conditioning (SFC), an ethologically valid model of SAD. In the present study, we extend these findings by evaluating the efficacy of sitagliptin in reducing social fear and preventing the development of comorbid depressive-like behavior in acid sphingomyelinase-deficient (ASM−/−) mice, a genetically defined model of antidepressant-resistant emotional behavior. Chronic oral administration of sitagliptin (100 mg/kg/day) significantly reduced social fear in both male and female ASM+/+ and ASM−/− mice following SFC. Notably, sitagliptin also prevented the emergence of depressive-like behavior in both genotypes, as well as the increase in anxiety-like behavior observed specifically in ASM−/− mice, two hallmark comorbidities in the SFC model. These findings indicate that sitagliptin exerts dual-action effects on both primary and comorbid behavioral symptoms of SAD, including in individuals resistant to conventional antidepressant treatment. Given its established clinical use and safety profile, sitagliptin may represent a promising candidate for repurposing as an early intervention in complex, treatment-resistant forms of SAD.

社交焦虑障碍（SAD）通常伴有共病性抑郁和对标准治疗的抵抗，但有效解决核心症状和共病症状的治疗策略仍然有限。我们之前证明了西格列汀，一种二肽基肽酶-4 （DPP4）抑制剂，通常用于治疗2型糖尿病，可以有效地减少社交恐惧条件作用（SFC）小鼠的社交恐惧，SFC是一种行为学上有效的SAD模型。在本研究中，我们通过评估西格列汀在酸性鞘磷脂酶缺乏（ASM-/-）小鼠（一种抗抑郁情绪行为的遗传定义模型）中减少社交恐惧和预防共病抑郁样行为发展的功效来扩展这些发现。长期口服西格列汀（100 mg/kg/天）显著降低了SFC后雄性和雌性ASM+/+和ASM-/-小鼠的社交恐惧，值得注意的是，西格列汀还阻止了两种基因型中出现的抑郁样行为，以及ASM-/-小鼠中观察到的焦虑样行为的增加，这是SFC模型中的两种标志性合并症。这些发现表明西格列汀对SAD的原发性和共病行为症状具有双重作用，包括对常规抗抑郁药物治疗有抵抗力的个体。鉴于其已确立的临床用途和安全性，西格列汀可能是一个有希望的候选药物，可作为复杂的、治疗抵抗型SAD的早期干预手段。

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引用次数: 0

Activation of 5-HT4 receptors reverses stress-induced dopamine system dysregulation 5-HT4受体的激活可逆转应激诱导的多巴胺系统失调

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.neuropharm.2025.110810

Olivia J. Yang , Stephanie M. Perez , Daniel J. Lodge

Stress can profoundly impact brain function, particularly in circuits regulating dopamine transmission. Increased mesolimbic dopamine activity is a well-documented consequence of stress exposure, contributing to maladaptive behavioral and cognitive outcomes. Previous studies have identified a multisynaptic circuit that modulates dopamine neuron population activity in the ventral tegmental area (VTA), highlighting potential intervention points for mitigating stress-induced dopamine dysregulation. One such target is the 5-hydroxytryptamine-4 receptor (5-HT4R), which is expressed in key brain regions involved in dopamine system regulation, making it a promising candidate for pharmacological intervention. Here, we demonstrate that the 5-HT4R agonist BIMU8 effectively restores normal dopamine system function following stress exposure without altering baseline dopamine population activity in control male rats. Interestingly, in female rats, BIMU8 increased dopamine neuron population activity specifically during proestrus and estrus, suggesting that estrogen may play a role in serotoninergic modulation of mesolimbic dopamine function. Intracranial administration of BIMU8 into multiple brain regions indicates that its effects may be mediated through modulation of activity in the nucleus accumbens (NAc). These findings highlight 5-HT4R activation as a potential strategy for normalizing stress-induced alterations in dopamine system function.

压力会深刻影响大脑功能，尤其是调节多巴胺传递的回路。中脑边缘多巴胺活动的增加是压力暴露的一个充分证明的后果，导致适应不良的行为和认知结果。先前的研究已经发现了一个调节腹侧被盖区（VTA）多巴胺神经元群活动的多突触回路，强调了减轻应激性多巴胺失调的潜在干预点。其中一个目标是5-羟色胺-4受体（5-HT4R），它在参与多巴胺系统调节的关键大脑区域表达，使其成为药物干预的有希望的候选者。在这里，我们证明了5-HT4R激动剂BIMU8可以有效地恢复应激暴露后正常的多巴胺系统功能，而不会改变对照雄性大鼠的基线多巴胺群活性。有趣的是，在雌性大鼠中，BIMU8增加了多巴胺神经元群的活性，特别是在发情前和发情期间，这表明雌激素可能在5 -羟色胺能调节中脑边缘多巴胺功能中发挥作用。脑内多个脑区注射BIMU8表明其作用可能通过调节伏隔核（NAc）的活性来介导。这些发现强调了5-HT4R激活是使应激诱导的多巴胺系统功能改变正常化的潜在策略。

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引用次数: 0

HCN channel inhibitor ZD7288 in the lateral septum attenuates methamphetamine-induced behavior sensitization and relapse 侧隔HCN通道抑制剂ZD7288可减轻甲基苯丙胺诱导的行为致敏和复发。

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology

Pub Date : 2025-12-18 DOI: 10.1016/j.neuropharm.2025.110811

Shishi Lai , Wenpei Zhang , Cailing Wang , Ying Xu , Shaolei Jiang , Xiaofei Deng , Mei Zhu , Gaowei Chen , Kuikui Zhou , Yingjie Zhu , Kunhua Wang

Drug addiction involves dysregulation in limbic circuits, with the lateral septum (LS) playing a critical role in regulating drug reward and behavioral sensitization. Although chronic methamphetamine (METH) upregulates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the LS, the therapeutic potential of targeting these channels remains unclear. Here, using pharmacological approaches in mice, we demonstrate that the HCN channel inhibitor ZD7288—administered either locally into the LS or systemically—attenuates METH-induced memory retrieval, the development and expression of locomotor sensitization, without impairing memory acquisition. Furthermore, ZD7288 reduced both METH self-administration acquisition and cue-induced reinstatement. These effects were associated with the normalization of METH-induced neuronal hyperexcitability in the LS. Importantly, ZD7288 did not affect natural reward processing, such as food consumption and social interaction. Our results identify LS HCN channels as potential therapeutic targets for METH use disorder.

药物成瘾涉及边缘回路失调，其中外侧隔（LS）在调节药物奖励和行为敏感化中起关键作用。尽管慢性甲基苯丙胺（METH）上调LS中超极化激活的环核苷酸门控（HCN）通道，但靶向这些通道的治疗潜力尚不清楚。在这里，我们通过药理学方法在小鼠中证明，HCN通道抑制剂zd7288在局部或系统给药的情况下，可以减弱甲基甲醚诱导的记忆检索、运动敏化的发展和表达，而不会损害记忆获取。此外，ZD7288减少了甲基安非他明自我给药的获得和线索诱导的恢复。这些效应与甲基苯丙胺诱导的LS神经元高兴奋性正常化有关。重要的是，ZD7288不影响自然奖励处理，如食物消费和社会互动。我们的研究结果确定LS HCN通道是冰毒使用障碍的潜在治疗靶点。

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引用次数: 0