Pharmacology Biochemistry and Behavior最新文献_第2页

EGR1-mediated repression of HDAC2 regulates BDNF-dependent kindling development in a mouse model of pentylenetetrazol-induced epilepsy egr1介导的HDAC2抑制在戊四唑诱导癫痫小鼠模型中调节bdnf依赖性点燃发育。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-17 DOI: 10.1016/j.pbb.2025.174131

Daisuke Ibi , Keisuke Ishida , Takaaki Kojima , Shuri Yoshida , Anna Suzuki , Serina Suzuki , Mai Yasui , Kotarou Shibuya , Moe Nakanishi , Tomoe Yamagami , Justin M. Saunders , Mario de la Fuente Revenga , Javier Gonzalez-Maeso , Masayuki Hiramatsu

Epilepsy is a chronic neurological condition characterized by recurrent seizures that affects millions of people worldwide. Recent studies have reported altered expression of early growth response 1 (Egr1), an activity-inducible immediate early gene, and histone deacetylase 2 (HDAC2), a regulator of gene transcription through the removal of acetyl groups from histone tails, in the hippocampus of epilepsy patients and animal models. Here, we investigated the roles of EGR1 and HDAC2 in pentylenetetrazol (PTZ)-induced seizures in kindled mice. Chronic PTZ treatment increased EGR1 and decreased HDAC2 expression in the hippocampus. Furthermore, EGR1 bound to the Hdac2 promoter and repressed its activity, but it had no effect when the predicted EGR1 binding site was deleted. Subsequently, we investigated the role of the HDAC2 in chemically induced kindling in mice with Hdac2 deletion. Hdac2 deletion suppressed PTZ-induced kindled seizures in mice compared with control mice. The upregulation of brain-derived neurotrophic factor (BDNF), a neurotrophin crucial for brain development, was observed in the hippocampi of control mice chronically treated with PTZ, but this increase was absent in mice with Hdac2 deletion. Additionally, continuous microinjection of recombinant BDNF protein into the ventricle accelerated kindling in mice with Hdac2 deletion, suggesting that HDAC2 contributes to the development of kindled seizures by regulating BDNF expression. In summary, HDAC2, which is negatively regulated by EGR1, induces BDNF expression in the hippocampus of PTZ-treated mice, resulting in the development of kindled seizures. These findings indicate that the EGR1-HDAC2-BDNF molecular pathway may serve as a therapeutic target in epilepsy.

癫痫是一种以反复发作为特征的慢性神经系统疾病，影响着全世界数百万人。最近的研究报道，在癫痫患者和动物模型的海马中，早期生长反应1 （Egr1）和组蛋白去乙酰化酶2 （HDAC2）的表达发生了改变。Egr1是一种活性诱导的直接早期基因，HDAC2是一种通过从组蛋白尾部去除乙酰基来调节基因转录的基因。在这里，我们研究了EGR1和HDAC2在戊四氮唑（PTZ）诱发的点燃小鼠癫痫发作中的作用。慢性PTZ治疗增加了海马中EGR1的表达，降低了HDAC2的表达。此外，EGR1与Hdac2启动子结合并抑制其活性，但当预测的EGR1结合位点被删除时，它没有影响。随后，我们研究了HDAC2在HDAC2缺失小鼠化学诱导点火中的作用。与对照组小鼠相比，缺失Hdac2可抑制ptz诱导的点燃性癫痫发作。脑源性神经营养因子（BDNF）是一种对大脑发育至关重要的神经营养因子，在长期接受PTZ治疗的对照小鼠海马中观察到上调，但在Hdac2缺失的小鼠中没有这种增加。此外，在Hdac2缺失小鼠脑室持续微量注射重组BDNF蛋白加速点燃，表明Hdac2通过调节BDNF表达参与点燃癫痫的发生。综上所述，受EGR1负调控的HDAC2可诱导ptz处理小鼠海马中BDNF的表达，导致点燃性癫痫发作的发生。这些发现表明EGR1-HDAC2-BDNF分子通路可能作为癫痫的治疗靶点。

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引用次数: 0

Noradrenergic inputs to the basolateral amygdala have bidirectional effects on coping behavior and neuronal activity in mice 基底外侧杏仁核的去肾上腺素能输入对小鼠的应对行为和神经元活动具有双向影响

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-14 DOI: 10.1016/j.pbb.2025.174130

Alexa R. Soares , Caroline Fai , Yann S. Mineur , Marina R. Picciotto

Norepinephrine (NE) signaling is disrupted in stress disorders, with insufficient NE signaling implicated in major depressive disorder and hyperactive NE signaling associated with post-traumatic stress disorder, suggesting that adequate mood regulation requires optimal NE levels. The basolateral amygdala (BLA) is a hub for stress processing and receives dense noradrenergic innervation from the locus coeruleus (LC), the primary noradrenergic nucleus in the brain. The relationship between LC activity and cognitive/behavioral function during fear conditioning has been described as an inverted U, in which moderate LC activity, and subsequent NE release, is required for adaptive coping to threats, while hyperactive LC-NE signaling drives maladaptive behavioral responses. We used fiber photometry to measure NE signaling in the mouse BLA during acute behavioral responses to escapable and inescapable stressors, and then used an optogenetic approach to stimulate the noradrenergic terminals in the BLA at different frequencies to evaluate effects on coping behavior and cFos expression in the LC-BLA circuit. We found that low-frequency stimulation of the circuit inhibited both passive coping and BLA neuronal activity, while high-frequency stimulation had the opposite effect; the behavioral effects were not mediated by sex, but the cFos effects were specific to males. This study represents an expansion of the inverted U framework to encompass LC-BLA signaling driving acute behavioral responses to stress.

去甲肾上腺素（NE）信号在应激障碍中被破坏，NE信号不足与重度抑郁症有关，NE信号过度活跃与创伤后应激障碍有关，这表明充分的情绪调节需要最佳的NE水平。基底外侧杏仁核（BLA）是应激处理的中枢，并接受来自蓝斑核（LC）的密集去肾上腺素能神经支配，蓝斑核是大脑中主要的去肾上腺素能核。在恐惧条件反射过程中，LC活动与认知/行为功能之间的关系被描述为倒U型，其中适度的LC活动和随后的NE释放是适应性应对威胁所必需的，而过度活跃的LC-NE信号则会导致适应不良的行为反应。我们采用纤维光度法测量小鼠BLA在可逃避和不可逃避应激源的急性行为反应中的NE信号，然后采用光遗传学方法以不同频率刺激BLA的去甲肾上腺素能末端，以评估对LC-BLA回路中应对行为和cFos表达的影响。研究发现，低频刺激对被动应对和BLA神经元活动均有抑制作用，而高频刺激则相反；行为效应不受性别的影响，但cfo效应是男性特有的。这项研究代表了倒U型框架的扩展，包括LC-BLA信号驱动对压力的急性行为反应。

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引用次数: 0

6-Methyl nicotine and nicotine have similar thermoregulatory and reinforcing effects in middle aged female rats with a history of nicotine vapor self-administration 6-甲基尼古丁和尼古丁对有尼古丁蒸气自我服用史的中年雌性大鼠具有相似的体温调节和强化作用。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-14 DOI: 10.1016/j.pbb.2025.174132

Michael A. Taffe , Tyra R. Coons , Tess A. Doran , Yanabel Grant , Sophia A. Vandewater

Rationale

The nicotine analog 6-methyl nicotine (6-MN) has recently appeared in non-tobacco nicotine delivery products, including oral pouches and e-cigarette liquids, in an apparent ploy to evade regulation of nicotine by the United States Food and Drug Administration or other public health agencies. Unfortunately, only minimal scientific information on the effects of 6-MN is available.

Objective

To determine the extent to which 6-MN produces nicotine-like effects on body temperature, wheel activity and nociception in laboratory rodents.

Methods

Middle-aged (starting at Post Natal Day 425) female Wistar rats were evaluated for rectal temperature, voluntary wheel activity, and nociceptive responses (warm water tail-withdrawal) to subcutaneous injection of nicotine (0.0, 0.8 mg/kg) or 6-methyl nicotine (6-MN; 0.0, 0.4, 0.8 mg/kg). Temperature and nociceptive responses to vapor inhalation of 6-MN [0–30 mg/mL in the propylene glycol (PG) vehicle] were assessed. Finally, the self-administration of 6-MN vapor was compared with nicotine vapor self-administration.

Results

6-MN decreased rectal temperature, suppressed wheel activity and induced modest nociceptive effects. The magnitude of the effect of 0.8 mg/kg 6-MN and 0.8 mg/kg nicotine were similar across all three assays. Vapor self-administration of 6-MN and nicotine was likewise comparable at a 10 mg/mL concentration.

Conclusion

6-MN administered by injection or by vapor inhalation produces behavioral and physiological effects that are very similar to those produced by nicotine in rats. It is therefore likely that detrimental health effects of 6-MN will be quite similar to those established for nicotine.

理由：尼古丁类似物6-甲基尼古丁（6-MN）最近出现在非烟草尼古丁输送产品中，包括口服袋和电子烟液，这显然是为了逃避美国食品和药物管理局或其他公共卫生机构对尼古丁的监管。不幸的是，关于6-MN影响的科学信息很少。目的：探讨6-MN对实验鼠类体温、轮活动和伤害感受产生尼古丁样影响的程度。方法：观察中年雌性Wistar大鼠（出生后425天开始）对尼古丁（0.0、0.8 mg/kg）或6-甲基尼古丁（6-MN; 0.0、0.4、0.8 mg/kg）皮下注射的直肠温度、自主轮活动和伤害反应（温水退尾）。评估6-MN[0-30 mg/mL丙二醇（PG）载药]蒸汽吸入的温度和伤害性反应。最后，将6-MN蒸汽自给药与尼古丁蒸汽自给药进行比较。结果：6-MN降低直肠温度，抑制轮活动，并引起适度的伤害效应。0.8 mg/kg 6-MN和0.8 mg/kg尼古丁的影响程度在所有三种分析中都是相似的。6-MN和尼古丁在10 mg/mL浓度下也具有可比性。结论：6-MN通过注射或蒸汽吸入对大鼠产生的行为和生理效应与尼古丁非常相似。因此，6-MN对健康的有害影响很可能与尼古丁的有害影响非常相似。

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引用次数: 0

Post-conditioning catecholaminergic antagonism fails to alter methamphetamine sensitization in mice 后处理儿茶酚胺能拮抗不能改变小鼠的甲基苯丙胺致敏性。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-11 DOI: 10.1016/j.pbb.2025.174129

A.S. Rauhut , K. Mehta , N. Fedorczak , J. Henderson , H. Holdaway , G.B. Rauhut

Single injection sensitization studies model the early transition to compulsive drug-seeking behavior, independent of other biological processes (e.g., drug tolerance). This paper examined a) the temporal persistence of (Experiment 1), and b) the role of catecholaminergic-mediated post-conditioning memory processes (Experiments 2a and 2b), in conditioned hyperactivity and behavioral sensitization after a single methamphetamine injection in male, Swiss Webster mice. Mice received either a single injection (intraperitoneal, i.p.) of physiological saline (vehicle) or methamphetamine (2.0 mg/kg) prior to a 30-minute locomotor activity session (Conditioning). Tests for conditioned hyperactivity (CR Test) and behavioral sensitization (Methamphetamine Challenge Test) occurred after a delay of 2 and 3 days (Immediate), 6 and 7 days (Short), 14 and 15 days (Moderate), or 27 and 28 days (Long), respectively. To assess the role of catecholaminergic activity, specifically dopamine D2 receptors (Experiments 2a) or β-adrenergic receptors (Experiment 2b) on memory consolidation, and its subsequent effect of conditioned hyperactivity and behavioral sensitization, the dopamine D2 antagonist, haloperidol (40 μg/kg), or the non-selective β-adrenergic (β1/β2) antagonist, propranolol (16 and 32 mg/kg), was administered immediately or 2.5 h after methamphetamine conditioning. Conditioned hyperactivity and behavioral sensitization were detected at all time points (Experiment 1). Furthermore, post-conditioning administration of haloperidol or propranolol failed to alter conditioned hyperactivity or behavioral sensitization (Experiment 2a and 2b). Collectively, these results suggest that the 1) conditioned and pharmacological responses persisted unchanged for equal durations, and 2) targeting the catecholaminergic system during memory consolidation did not disrupt induction of either conditioning hyperactivity or sensitization.

单次注射致敏研究模拟了早期过渡到强迫性药物寻求行为，独立于其他生物过程（如药物耐受性）。本文研究了a)时间持久性（实验1）和b)儿茶酚胺能介导的后条件反射记忆过程（实验2a和2b）在雄性瑞士韦氏小鼠注射一次甲基苯丙胺后条件亢进和行为致敏中的作用。小鼠在30分钟的运动活动（调节）之前接受生理盐水（对照品）或甲基苯丙胺（2.0 mg/kg）的单次注射（腹腔注射，i.p.）。条件亢进（CR试验）和行为致敏（甲基苯丙胺激发试验）分别在延迟2和3 天（立即）、6和7 天（短）、14和15 天（中度）或27和28 天（长）后进行。为了评估儿茶酚胺能活性，特别是多巴胺D2受体（实验2a）或β-肾上腺素能受体（实验2b）在记忆巩固中的作用，及其随后对条件性多动和行为致敏的影响，在甲基苯丙胺条件作用后立即或2.5 小时给予多巴胺D2拮抗剂氟哌啶醇（40 μg/kg）或非选择性β-肾上腺素能（β1/β2）拮抗剂心得安（16和32 mg/kg）。在所有时间点均检测到条件性多动和行为致敏（实验1）。此外，条件反射后给予氟哌啶醇或心得安也不能改变条理性多动或行为致敏（实验2a和2b）。总的来说，这些结果表明1)条件反应和药理学反应在相同的时间内保持不变，2)在记忆巩固期间靶向儿茶酚胺系统不会破坏条件反射多动或致敏的诱导。

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引用次数: 0

Simultaneous modulation of 5-HT6 and SERT by MM394: a dual-target ligand providing neuroprotection against amyloid-β toxicity, memory preservation, and alleviation of BPSD symptoms MM394同时调节5-HT6和SERT：一种双靶点配体，提供抗淀粉样蛋白-β毒性、记忆保存和减轻BPSD症状的神经保护。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-10 DOI: 10.1016/j.pbb.2025.174128

Agata Siwek , Monika Marcinkowska , Barbara Mordyl , Monika Głuch-Lutwin , Małgorzata Wolak , Magdalena Jastrzębska-Więsek , Natalia Wilczyńska-Zawal , Elżbieta Wyska , Katarzyna Szafrańska , Anna Wesołowska , Marcin Kołaczkowski

In addition to cognitive decline, 90 % of dementia patients experience behavioral and psychological symptoms of dementia, for which no safe and effective pharmacotherapy currently exists. Our study aimed to determine the therapeutic potential of the new dual 5-HT₆/SERT-acting ligand MM394 in the context of pro-cognitive and neuroprotective properties, as well as its effects on behavioral symptoms and mood disorders in patients diagnosed with Alzheimer's disease. We performed in vitro experiments to examine the neuroprotective and antioxidant properties of MM394, as well as in vivo studies on male rats to evaluate its pharmacokinetics and potential in behavioral modulation of memory and mood. Following this, we attempted to determine the molecular mechanism of action of the dual 5-HT₆/SERT targeting compound in ex vivo experiments using rats' hippocampus and prefrontal cortex. The results of our study in the HT-22 cell line support the potential of MM394 to target excitotoxicity and oxidative stress, which play a key role in neurodegeneration. Furthermore, the compound exhibits antidepressant-like activity in the forced swim test and counteracts the memory impairments caused by MK-801 in the novel object recognition assessment in rats. Ex vivo findings demonstrate that MM394 modulates mTOR and ERK1/2 phosphorylation in the studied brain areas and increases the level of BDNF in the hippocampus when co-administered with MK-801 in the novel object recognition test. As a result of these findings, MM394 may be useful as a therapeutic for BPSD, which should be further explored.

除了认知能力下降外，90% %的痴呆患者还会出现痴呆的行为和心理症状，目前尚无安全有效的药物治疗方法。我们的研究旨在确定新的双5-HT6/ sert作用配体MM394在促进认知和神经保护特性方面的治疗潜力，以及它对阿尔茨海默病患者行为症状和情绪障碍的影响。我们通过体外实验研究了MM394的神经保护和抗氧化特性，并在雄性大鼠体内研究了其药代动力学及其在记忆和情绪行为调节方面的潜力。在此基础上，我们利用大鼠海马和前额皮质进行离体实验，试图确定5-HT6/SERT双重靶向化合物的分子作用机制。我们在HT-22细胞系的研究结果支持MM394靶向兴奋性毒性和氧化应激的潜力，这在神经退行性变中起关键作用。此外，该化合物在强迫游泳测试中表现出抗抑郁样活性，并在新物体识别评估中抵消MK-801引起的大鼠记忆障碍。离体研究结果表明，当在新的目标识别测试中与MK-801共同使用时，MM394调节所研究脑区域的mTOR和ERK1/2磷酸化，并增加海马中BDNF的水平。由于这些发现，MM394可能是一种有用的治疗BPSD的药物，值得进一步探索。

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引用次数: 0

Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects 长期巯基佩拉嗪治疗阿尔茨海默病小鼠Tg4-42模型：治疗潜力与不良反应

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-09 DOI: 10.1016/j.pbb.2025.174127

Lisa Katharina Ruoff , Irina Wanda Helene Bänfer , Djavid Elias Liedtke , Sofie Elena China , Jens Wiltfang , Thomas A. Bayer , Sören Frederik Bock , Friederike Spandau , Caroline Bouter , Nicola Beindorff , Yvonne Bouter

Background

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.

Aims

This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.

Methods

Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, ¹⁸F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.

Results

Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.

Conclusion

Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.

背景：阿尔茨海默病（AD）是一种以进行性认知能力下降和行为障碍为特征的神经退行性疾病。ththylperazine是一种多巴胺受体拮抗剂，具有止吐和抗多巴胺能的特性，被认为是一种潜在的治疗AD的药物。然而，其对AD患者认知功能的影响尚不清楚。目的：本研究探讨噻乙拉嗪对a β4-42过表达和进行性神经退行性变模型Tg4-42小鼠的记忆、焦虑样行为、运动功能和AD病理的长期影响。此外，我们还研究了长时间噻乙拉嗪治疗对健康成年C57BL/6J野生型（WT）小鼠的行为结局和脑糖代谢的影响。方法：Tg4-42和WT小鼠从10 周龄开始，每天给予10 mg/kg噻乙基拉嗪，持续6 个月。在7.5 个月时进行记忆、焦虑相关和运动测试。免疫组织化学分析量化了对Aβ病理、神经发生、神经元数量和神经炎症的影响。此外，18F-FDG-PET成像用于评估治疗后WT小鼠的代谢活性。结果：噻乙拉嗪可改善Tg4-42小鼠的识别记忆，并具有抗焦虑作用。然而，它损害了Morris水迷宫（MWM）的空间学习，减少了运动，并没有减轻运动障碍。未观察到对神经元丢失或神经炎症的影响。在WT小鼠中，ththylperazine改变了MWM的学习过程，正如搜索策略的改变所表明的那样，诱导了低代谢和增加了神经发生。结论：尽管ththylperazine对Tg4-42有轻微的认知益处，但其对学习策略和运动的不利影响使其作为AD治疗选择的潜力受到质疑。

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引用次数: 0

Adolescent stress differentially modulates the affective, psychomotor, and neural responses to a first amphetamine exposure in male Wistar rats 青春期应激对雄性Wistar大鼠初次接触安非他明的情感、精神运动和神经反应有差异调节。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-11-05 DOI: 10.1016/j.pbb.2025.174126

Andrey Sequeira-Cordero , Juan C. Brenes

The initial neurobehavioral adaptations following the first drug exposure may underlie the transition from recreational to compulsive use in vulnerable individuals. Compelling evidence indicates that early life adversity (ELA) is a significant risk factor for drug dependence. To better understand the relationship between ELA and initial drug experiences, we investigated whether chronic unpredictable stress (CUS) during adolescence modifies the affective (ultrasonic vocalizations, USVs), psychomotor (rearing and locomotion), and neural responses to a single dose of amphetamine in rats. CUS alone led to open-field hyperactivity and reduced flat USVs. CUS significantly blunted amphetamine-induced hyperactivity –suggesting a cross-tolerance effect– while it augmented amphetamine-induced appetitive 50-kHz calls, indicating a cross-sensitization effect. These results might suggest that CUS increases the rewarding and reduces the anxiogenic properties of initial amphetamine experience. At the neural level, amphetamine increased the expression of corticotropin-releasing factor (Crf)-related genes and the 2B subunit of the N-methyl-d-aspartate glutamate receptor (Nr2b) in a region-dependent manner. CUS upregulated the expression of brain-derived neurotrophic factor (Bdnf) in the medial prefrontal cortex (mPFC) and actin-related protein 2 (Arp2) in the nucleus accumbens (NAc). A cross-tolerance effect was observed for Bdnf, tropomyosin receptor kinase B (TrkB), and Cofilin-1 in the mPFC. Conversely, the expression of Rho GTPase-activating protein 32 (P250gap), cAMP-response element binding protein (Creb), and DNA methyltransferase 3A (Dnmt3a) was cross-sensitized in the NAc. The coexistence of cross-sensitization and cross-tolerance neurobehavioral effects between CUS and amphetamine supports the idea that ELA can simultaneously blunt and heighten different brain substrates, collectively increasing the risk of drug dependence.

在易受伤害的个体中，初次接触药物后最初的神经行为适应可能是由娱乐性向强迫性使用转变的基础。令人信服的证据表明，早期生活逆境（ELA）是药物依赖的重要危险因素。为了更好地理解ELA与初始药物体验之间的关系，我们研究了青春期慢性不可预测应激（CUS）是否会改变大鼠对单剂量安非他明的情感（超声波发声，usv）、精神运动（饲养和运动）和神经反应。单独使用CUS可导致开阔区多动和平坦usv减少。CUS显著减弱了安非他明诱导的多动症，这表明了交叉耐受效应，同时它增强了安非他明诱导的50千赫的食欲呼叫，这表明了交叉致敏效应。这些结果可能表明，CUS增加了安非他命初始体验的奖励性，减少了焦虑性。在神经水平上，安非他明以区域依赖的方式增加促肾上腺皮质激素释放因子（Crf）相关基因和n-甲基-d-天冬氨酸谷氨酸受体（Nr2b） 2B亚基的表达。CUS上调内侧前额叶皮层（mPFC）脑源性神经营养因子（Bdnf）和伏隔核（NAc）肌动蛋白相关蛋白2 （Arp2）的表达。在mPFC中观察到Bdnf、原肌球蛋白受体激酶B （TrkB）和Cofilin-1的交叉耐受效应。相反，Rho gtpase激活蛋白32 （P250gap）、camp反应元件结合蛋白（Creb）和DNA甲基转移酶3A （Dnmt3a）的表达在NAc中交叉增敏。CUS和安非他明之间共存的交叉致敏和交叉耐受神经行为效应支持了ELA可以同时钝化和增强不同的脑底物，共同增加药物依赖风险的观点。

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引用次数: 0

Dual orexin receptor antagonists in insomnia: Toward a new therapeutic paradigm 双重食欲素受体拮抗剂治疗失眠：迈向新的治疗范式。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-10-24 DOI: 10.1016/j.pbb.2025.174117

Shigeyuki Chaki , Yumiko Imadera

Although three dual orexin receptor antagonists (DORAs), suvorexant, lemborexant, and daridorexant, are currently available and widely used to treat insomnia, the differences in their elimination half-lives are not sufficient. As a result, clinicians have limited ability to tailor therapy to individual sleep complaints. The emergence of vornorexant, with a notably short half-life comparable to that of zolpidem, may substantially expand the clinical utility of DORAs. This broader spectrum of pharmacokinetic profiles enables more individualized treatment strategies that align with patients' specific sleep complaints. This approach, in turn, potentially reshapes the therapeutic paradigm of insomnia management. However, several challenges remain to be addressed in order to fully realize the clinical potential of DORAs. This review identifies four key challenges requiring resolution to advance their optimal use in clinical practice.

虽然目前有三种双食欲素受体拮抗剂（DORAs）， suvorexant， lemborexant和daridorexant被广泛用于治疗失眠，但它们的消除半衰期的差异还不够。因此，临床医生针对个人睡眠问题量身定制治疗的能力有限。vornorexant的出现，与唑吡坦相比，其半衰期明显较短，可能会大大扩大dora的临床应用。这种更广泛的药代动力学谱使更个性化的治疗策略与患者的特定睡眠抱怨保持一致。这种方法，反过来，有可能重塑失眠管理的治疗范式。然而，为了充分发挥DORAs的临床潜力，仍有几个挑战有待解决。本综述确定了需要解决的四个关键挑战，以促进其在临床实践中的最佳应用。

引用次数: 0

Intranasal LAG3 antibody infusion induces microglia-dependent antidepressant effect by mobilizing astrocytic P2Y1R-mediated BDNF synthesis in the hippocampus 鼻内滴注LAG3抗体通过动员星形胶质细胞p2y1r介导的海马BDNF合成，诱导小胶质细胞依赖性抗抑郁作用。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-10-15 DOI: 10.1016/j.pbb.2025.174114

Wenfeng Hu , Minxiu Ye , Qijun Dai , Micona Sun , Rongrong Song , Xu Lu , Chao Huang , Lin Zhang , Rongrong Yang

Intranasal infusion of lymphocyte-activating gene-3 antibody (In-LAG3-Ab) has microglia-dependent antidepressant effects, but the underlying mechanism remains unclear. Since microglia can interact with astrocytes through purinergic signaling, we hypothesize that microglia-driven purinergic signaling may mediate the antidepressant effect of In-LAG3-Ab. The results showed that a single In-LAG3-Ab infusion in chronically stressed mice produced both an antidepressant effect and increased adenosine triphosphate (ATP) levels in the dentate gyrus, both of which were suppressed by chemogenetic inhibition of microglia in the dentate gyrus. Depletion of ATP or non-specific antagonism of purinergic receptors abolished the antidepressant effect of In-LAG3-Ab. Specific inhibition of purinergic 2Y1 receptors (P2Y1Rs), but not other purinergic receptors, in the hippocampus or conditional depletion of P2Y1Rs in astrocytes also abolished the antidepressant effect of In-LAG3-Ab. Brain-derived neurotrophic factor (BDNF) may act downstream of astrocytic P2Y1Rs to mediate the antidepressant effect of In-LAG3-Ab, as (i) chemogenetic inhibition of microglia in the dentate gyrus, specific deletion of astrocytic P2Y1Rs, and depletion of endogenous ATP abolished the reversal effect of In-LAG3-Ab on chronic stress-induced decreases in BDNF in the dentate gyrus, and (ii) infusion of BDNF-Ab into the hippocampus abolished the antidepressant effect of In-LAG3-Ab. These results suggest that astrocytic P2Y1R signaling associated with microglia stimulation may mediate the antidepressant effect of In-LAG3-Ab through BDNF.

鼻内输注淋巴细胞活化基因-3抗体（In-LAG3-Ab）具有小胶质细胞依赖性抗抑郁作用，但其潜在机制尚不清楚。由于小胶质细胞可以通过嘌呤能信号传导与星形胶质细胞相互作用，我们假设小胶质细胞驱动的嘌呤能信号传导可能介导In-LAG3-Ab的抗抑郁作用。结果表明，长期应激小鼠单次输注in - lag3 - ab可产生抗抑郁作用，并增加齿状回中三磷酸腺苷（ATP）水平，这两种作用均通过齿状回小胶质细胞的化学发生抑制而受到抑制。ATP耗竭或嘌呤能受体的非特异性拮抗作用可消除In-LAG3-Ab的抗抑郁作用。特异性抑制海马嘌呤能2Y1受体（P2Y1Rs），而不抑制其他嘌呤能受体，或星形胶质细胞中P2Y1Rs的条件缺失也会消除in - lag3 - ab的抗抑郁作用。脑源性神经营养因子（BDNF）可能作用于星形胶质细胞P2Y1Rs的下游，介导in- lag3 - ab的抗抑郁作用，因为(i)齿状回小胶质细胞的化学发生抑制、星形胶质细胞P2Y1Rs的特异性缺失和内源性ATP的消耗消除了in- lag3 - ab对慢性应激诱导的齿状回BDNF减少的逆转作用，以及（ii）将BDNF- ab输注到海马中消除了in- lag3 - ab的抗抑郁作用。这些结果表明星形细胞P2Y1R信号通路与小胶质细胞刺激相关，可能通过BDNF介导In-LAG3-Ab的抗抑郁作用。

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Challenges in cross-test comparison of anxiety-related outcomes in rodents: A network meta-analysis 啮齿动物焦虑相关结果交叉测试比较的挑战：网络荟萃分析。

IF 2.5 3区心理学 Q1 BEHAVIORAL SCIENCES

Pharmacology Biochemistry and Behavior

Pub Date : 2025-10-13 DOI: 10.1016/j.pbb.2025.174116

Didem Derici Yıldırım , Özge Selin Çevik , Erdal Horata , Coşar Uzun

Anxiety-like complex behavioral and psychological constructs are difficult to evaluate in rodents. Many studies have investigated which techniques are appropriate for measuring anxiety and related physiological parameters. Here, we used network meta-analysis to compare the current methods of assessing anxiety. We performed a comprehensive review and network meta-analysis by searching PubMed, EMBASE, the Cochrane Library, SCOPUS, and Web of Science for studies involving rodents with anxiety-related behaviors undergoing behavioral tests with certain keywords: The common parameters that emerged were total distance traveled, fecal boli count, and rearing behavior. In the 46 studies reviewed, the open-field test (OFT) and elevated plus maze (EPM) test appeared most often (in 45 and 43 studies, respectively), while the light–dark box (LDB) and elevated zero maze tests appeared less frequently (in two studies and one study, respectively Subsequently, the tests were ranked based on their likelihood of being the most effective measure for each outcome. For total distance traveled, the OFT showed a significant disadvantage over the EPM and LDB. For fecal boli, there was a significant difference between the LDB and OFT. There were no variations between tests in terms of rearing. Our findings reinforce the importance of considering each behavioral test's unique characteristics when selecting appropriate measures for anxiety-like behaviors. Researchers should exercise caution when interpreting single-measure outcomes and adopt a holistic approach that integrates multiple test results to achieve reliable and relevant conclusions. Network meta-analysis is a powerful tool for identifying the highlights, complexities, and inconsistencies of anxiety-related behaviors in rodents in preclinical anxiety models.

在啮齿类动物中，类似焦虑的复杂行为和心理结构难以评估。许多研究调查了哪些技术适合测量焦虑和相关的生理参数。在这里，我们使用网络元分析来比较目前评估焦虑的方法。我们通过检索PubMed、EMBASE、Cochrane图书馆、SCOPUS和Web of Science，对涉及焦虑相关行为的啮齿动物的研究进行了全面的回顾和网络荟萃分析，并对某些关键词进行了行为测试：出现的常见参数是总行走距离、粪便计数和饲养行为。在回顾的46项研究中，开放式测试（OFT）和高架迷宫（EPM）测试出现的频率最高（分别在45项和43项研究中），而光暗箱测试（LDB）和高架零迷宫测试出现的频率较低（分别在两项研究和一项研究中）。随后，根据它们对每个结果最有效的测量方法的可能性对这些测试进行了排名。对于总行驶距离，OFT比EPM和LDB表现出明显的劣势。对于粪肠，LDB和OFT之间存在显著差异。在饲养方式方面，试验之间没有差异。我们的研究结果强调了在选择合适的焦虑类行为测量方法时，考虑每个行为测试的独特特征的重要性。研究人员在解释单一测量结果时应谨慎行事，并采用综合多个测试结果的整体方法，以获得可靠和相关的结论。网络荟萃分析是识别临床前焦虑模型中啮齿动物焦虑相关行为的亮点、复杂性和不一致性的有力工具。

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引用次数: 0