Addiction neuroscience最新文献_第4页

Predator scent stress reduces oxycodone self-administration and the nucleus accumbens dopamine response to oxycodone in female rats 捕食者气味压力降低雌性大鼠羟考酮自我给药和伏隔核多巴胺对羟考酮的反应

Addiction neuroscience

Pub Date : 2025-05-24 DOI: 10.1016/j.addicn.2025.100210

Courtney S. Wilkinson , Siya Bhutani , Wonn Pyon , Marek Schwendt , Lori A. Knackstedt

Post-traumatic stress disorder (PTSD) develops in a sub-population of people exposed to trauma and is highly comorbid with opioid use disorder (OUD). The neurobiology of comorbid PTSD+OUD, especially with respect to sex differences, is poorly understood. Here we investigated the sex-specific effects of predator scent stress on intravenous (IV) oxycodone self-administration (SA), cue-primed reinstatement, and pre- and post-stress corticosterone (CORT) concentrations. Upon detecting effects of stress on oxycodone IVSA, the nucleus accumbens (NA) dopamine response to oxycodone was assessed. Male and female rats received a single 10-minute exposure to the predator scent TMT or the control condition. One week later, rats were tested for anxiety-like behavior on the elevated plus maze and underwent oxycodone IVSA, instrumental extinction, and a cue-primed reinstatement test. In a separate cohort of only female rats, the NA core dopamine response to IV oxycodone (0, 0.25, 0.5 mg/kg) was assessed using fiber photometry. TMT increased anxiety-like behavior one week later in male and female rats. Baseline CORT was negatively correlated with anxiety-like behavior in males. TMT exposure reduced oxycodone intake exclusively in females, with no effects on instrumental extinction or cue-primed reinstatement in either sex. Female rats demonstrated a dose-dependent increase in NA core dopamine signal following oxycodone administration that was blunted by a history of TMT exposure. These results indicate that TMT exposure diminishes the NA core dopamine response to oxycodone in females, reducing oxycodone IVSA. These results are consistent with stress-induced reward insensitivity that has been observed following stress in both rodents and humans.

创伤后应激障碍（PTSD）在暴露于创伤的人群中发展，并与阿片类药物使用障碍（OUD）高度共病。PTSD+OUD共病的神经生物学，特别是在性别差异方面，知之甚少。在这里，我们研究了捕食者气味应激对静脉注射（IV）羟考酮自我给药（SA）、线索启动恢复以及应激前和应激后皮质酮（CORT）浓度的性别特异性影响。在检测应激对羟考酮IVSA的影响后，评估伏隔核（NA）多巴胺对羟考酮的反应。雄性和雌性大鼠分别在捕食者气味TMT或对照条件下暴露10分钟。一周后，大鼠在高架+迷宫中进行焦虑样行为测试，并进行羟考酮IVSA、工具消失和线索启动恢复测试。在单独的雌性大鼠队列中，使用纤维光度法评估静脉注射羟考酮（0、0.25、0.5 mg/kg）时NA核心多巴胺的反应。一周后，TMT增加了雄性和雌性大鼠的焦虑样行为。基线CORT与男性焦虑样行为呈负相关。TMT暴露减少了氧可酮的摄入量，仅在女性中，对任何性别的工具性灭绝或线索启动恢复都没有影响。雌性大鼠表现出羟考酮给药后NA核心多巴胺信号的剂量依赖性增加，该信号因TMT暴露史而减弱。这些结果表明，TMT暴露降低了雌性NA核心多巴胺对羟考酮的反应，降低了羟考酮IVSA。这些结果与在啮齿动物和人类中观察到的压力引起的奖励不敏感一致。

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引用次数: 0

Genomic and behavioral signatures of selection for ethanol preference from the heterogeneous stock collaborative cross mice – The central nucleus of the amygdala 异种种群合作杂交小鼠乙醇偏好选择的基因组和行为特征——杏仁核中央核

Addiction neuroscience

Pub Date : 2025-05-07 DOI: 10.1016/j.addicn.2025.100209

Justin Q. Anderson , Priscila Darakjian , Robert Hitzemann , Rita Cervera-Juanes , Kip D. Zimmerman , Cheryl Reed , Denesa Lockwood , Angela R. Ozburn , Tamara J. Phillips

Alcohol use disorder (AUD) is a complex disease with heritability of ∼0.5, indicating genetic and non-genetic factors contribute to risk. Identifying gene expression networks contributing to risk using post-mortem human brain tissue has the limitation of conflating risk for AUD with consequences of alcohol use. We leveraged mice selectively bred for differential ethanol preference from a highly genetically diverse population to overcome this limitation. Ethanol intake was highly correlated with preference, high-preferring (HP) mice consumed more sweet- but not bitter-tasting solutions compared to low-preferring (LP) mice, and the lines did not differ in rate of ethanol elimination. Adult, ethanol-naïve HP and LP mice contributed tissue from the central nucleus of the amygdala (CeA), a region critical to ethanol preference and intake. Single-nuclei and bulk RNA sequencing data were used to identify cell types and transcriptome changes related to selective breeding for differential risk for ethanol preference. Single nuclei analysis identified populations of inhibitory (∼48 % of cells) and excitatory (∼23 %) neurons, and non-neuronal (∼29 %) cells, but no differences in cell-type composition or gene expression were identified between the lines. Bulk CeA analysis identified differences between the lines for: (1) gene expression (2996 genes), (2) expression variability (426 genes), and (3) wiring (407 significant gene-gene correlations). Overall, lower variance was found in the HP line. Reduced gene-gene correlation, also found in HP mice, suggested that selection for high preference induced changes in transcriptional regulation resulting in reduced connectivity, specific to gene networks enriched in markers for inhibitory neurons expressing Isl1 and Tac1.

酒精使用障碍（AUD）是一种复杂的疾病，遗传率为~ 0.5，表明遗传和非遗传因素会导致风险。使用死后的人类脑组织识别与风险相关的基因表达网络具有将AUD风险与饮酒后果混为一谈的局限性。为了克服这一限制，我们从一个高度遗传多样性的群体中选择性地培育出不同乙醇偏好的小鼠。乙醇摄入量与偏好高度相关，高偏好（HP）小鼠比低偏好（LP）小鼠消耗更多甜味而不是苦味的溶液，并且两系在乙醇消除率上没有差异。成年，ethanol-naïve HP和LP小鼠提供了来自杏仁核中央核（CeA）的组织，这是对乙醇偏好和摄入至关重要的区域。单核和大量RNA测序数据用于鉴定细胞类型和转录组变化与乙醇偏好差异风险的选择性育种相关。单核分析鉴定出抑制性（约48%的细胞）和兴奋性（约23%）神经元以及非神经元（约29%）细胞群，但在细胞系之间没有发现细胞类型组成或基因表达的差异。大量CeA分析确定了品系之间的差异：(1)基因表达（2996个基因），(2)表达变异性（426个基因），(3)接线（407个显著的基因基因相关性）。总体而言，在HP系中发现了较低的方差。在HP小鼠中也发现了基因相关性的降低，这表明高偏好的选择诱导了转录调控的变化，导致连通性降低，特异性地针对表达Isl1和Tac1的抑制性神经元标记中富集的基因网络。

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引用次数: 0

EcoHIV infection effects on cocaine seeking and neuroimmune responses in male mice depend on cocaine exposure pattern EcoHIV感染对雄性小鼠可卡因寻求和神经免疫反应的影响取决于可卡因暴露模式

Addiction neuroscience

Pub Date : 2025-04-22 DOI: 10.1016/j.addicn.2025.100208

Mark D. Namba , Qiaowei Xie , Kyewon Park , Joshua G. Jackson , Jacqueline M. Barker

Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) remain persistent public health dilemmas throughout the world. Cocaine seeking increases over a protracted period of abstinence, an effect known as the incubation of craving. Little is known about how HIV may modulate this process. Thus, we sought to examine the impact of chronic HIV infection on the incubation of cocaine craving and associated changes in the expression levels of central neuroimmune and peripheral immune substrates. Here, male mice were inoculated with EcoHIV, which is a chimeric HIV-1 construct that produces chronic HIV infection in mice. Mice were conditioned with cocaine daily or intermittently in a conditioned place preference (CPP) paradigm, followed by 1 or 21 days of forced abstinence prior to assessing preference for the cocaine-paired chamber. Mice conditioned daily exhibited potentiated incubation of cocaine CPP after 21 days of abstinence, and EcoHIV increased cocaine CPP across the test session at both abstinence timepoints. Conversely, EcoHIV-infected mice conditioned intermittently showed higher cocaine seeking after 1 day of abstinence compared to 21 days. Analysis of corticolimbic CX3CL1-CX3CR1 and glutamate receptor expression revealed a positive relationship between cocaine seeking and medial prefrontal cortex (mPFC) CX3CL1 and GluA1, as well as a nucleus accumbens (NAc) GluN2A expression. Moreover, examination of peripheral immune markers showed that the effect of abstinence and EcoHIV infection on these measures depended on the cocaine exposure regimen. Altogether, these results highlight the importance of cocaine abstinence and exposure pattern as critical variables that modulate HIV-associated neuroimmune outcomes and relapse vulnerability.

可卡因使用障碍（CUDs）和人类免疫缺陷病毒（HIV）仍然是世界各地持续存在的公共卫生难题。在一段较长时间的戒断期间，对可卡因的需求会增加，这种效应被称为渴望的潜伏期。人们对HIV如何调节这一过程知之甚少。因此，我们试图研究慢性HIV感染对可卡因渴求潜伏期的影响，以及中枢神经免疫和外周免疫底物表达水平的相关变化。在这里，雄性小鼠接种了EcoHIV，这是一种嵌合HIV-1构建体，在小鼠中产生慢性HIV感染。小鼠在条件位置偏好（CPP）模式下每天或间歇性地使用可卡因，然后在评估对可卡因配对室的偏好之前进行1天或21天的强制戒断。戒断21天后，每天接受条件训练的小鼠表现出增强的可卡因CPP潜伏期，EcoHIV在两个戒断时间点的整个测试过程中都增加了可卡因CPP。相反，与21天相比，间歇性的ecohiv感染小鼠在禁欲1天后表现出更高的可卡因寻求率。皮质边缘CX3CL1- cx3cr1和谷氨酸受体表达分析显示，可卡因寻求与内侧前额叶皮层（mPFC） CX3CL1和GluA1以及伏隔核（NAc） GluN2A表达呈正相关。此外，外周免疫标志物的检测表明，戒断和EcoHIV感染对这些指标的影响取决于可卡因暴露方案。总之，这些结果强调了可卡因戒断和暴露模式作为调节hiv相关神经免疫结果和复发易感性的关键变量的重要性。

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引用次数: 0

Methamphetamine produces behavioral flexibility deficits that are attenuated by COX-2 inhibition in both male and female rats 甲基苯丙胺在雄性和雌性大鼠中产生行为灵活性缺陷，这种缺陷通过抑制COX-2而减轻

Addiction neuroscience

Pub Date : 2025-04-01 DOI: 10.1016/j.addicn.2025.100207

Amanda M. Acuña , Serena E. Rodarte , Skylar Bickley , Erin K. Nagy , Emma Peacock , Annabel Carlson , Paula F. Overby , M. Foster Olive

Methamphetamine (METH) Use Disorder (MUD) and METH-related overdose deaths continue to rise in the United States and elsewhere. Patients with MUD experience cognitive inflexibility, which conveys a vulnerability to continued addictive behaviors and relapse. Neuroinflammation is present in both brain tissue and serum following METH use and appears to play a role in cognitive deficits. The current study sought to investigate the ability of an anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor, parecoxib (PXB), to attenuate METH-induced deficits in behavioral flexibility in male and female rats. Rats were given binge-like access (96 hrs/week/3 weeks) to METH via intravenous self-administration (IVSA) at 0.05 mg/kg/infusion, or saline as a control. Behavioral flexibility was assessed using the Attentional Set Shifting Task (ASST) prior to and three weeks following the cessation of drug access, with PXB administered for the last 7 days of abstinence. Difference scores for ASST performance were calculated (post drug/treatment – baseline) and compared between groups: saline-saline, saline-PXB, METH-saline, METH-PXB. Rats that self-administered METH required more trials to reach criterion in the extradimensional shift (ED) part of ASST than they did prior to METH, indicating a deficit in attentional set shifting in both sexes following METH. Strikingly, rats treated with PXB following METH IVSA performed similarly to controls, suggesting an attenuation of behavioral deficits. Sex differences in the simple discrimination (SD) part of the task were also observed, with METH-saline females exhibiting deficits that were attenuated by PXB. These findings reinforce the argument that pharmacologically targeting neuroimmune responses to METH may facilitate recovery from MUD.

在美国和其他地方，甲基苯丙胺（冰毒）使用障碍（MUD）和与冰毒有关的过量死亡人数继续上升。MUD患者的认知缺乏灵活性，这传达了持续成瘾行为和复发的脆弱性。使用冰毒后，脑组织和血清中都存在神经炎症，似乎在认知缺陷中起作用。目前的研究旨在研究抗炎环氧化酶-2 （COX-2）抑制剂parecoxib （PXB）在雄性和雌性大鼠中减轻甲基甲氧嘧啶引起的行为灵活性缺陷的能力。大鼠通过静脉自我给药（IVSA）以0.05 mg/kg/次滴注，或生理盐水作为对照，给毒（96小时/周/3周）。在停药前和停药后三周，使用注意力集中转移任务（注意集转移任务）评估行为灵活性，并在停药的最后7天给予PXB。计算（药物后/治疗后-基线）皮肤助理试验的差异评分，并比较两组：saline-saline， salt - pxb, METH-saline, METH-PXB。与服用冰毒之前相比，自我服用冰毒的大鼠需要更多的试验才能达到外维转移（ED）部分的标准，这表明在冰毒后，两性的注意力集中转移出现了缺陷。引人注目的是，在冰毒IVSA后接受PXB治疗的大鼠表现与对照组相似，表明行为缺陷的减弱。简单辨别（SD）部分的性别差异也被观察到，服用冰毒盐水的女性表现出PXB减轻的缺陷。这些发现加强了药理学上针对甲基苯丙胺的神经免疫反应可能促进MUD恢复的观点。

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引用次数: 0

A translational framework for personalizing intervention models to prevent substance use disorder 预防药物使用障碍的个性化干预模式转化框架

Addiction neuroscience

Pub Date : 2025-03-28 DOI: 10.1016/j.addicn.2025.100206

Diana Fishbein , Emma Jane Rose

This introductory paper frames the Addiction Neuroscience Special Issue on “Neuroprevention for Substance Use” by describing a transdisciplinary neuroscience approach to understanding and intercepting developmental pathways to addiction. Our integrative model derives from biomedical research that provides clues as to the underlying mechanisms of effects of existing and novel evidenced-based preventive strategies. A supportive translational research infrastructure for a “community” of crosscutting scientists guides this work to inform the design of interventions that more directly target underlying generators of the phenomenon we aim to prevent; i.e., poor biobehavioral health leading to increased propensity to substance use initiation, escalation, and addiction. Advancing this approach to address the gaps in substance use prevention research involves identifying common ground and priorities, stimulating cross-disciplinary communication, sharing etiological findings, applying multilevel methodologies to analyzing integrated datasets, and determining ways in which collaborative investigations can lead to a better understanding of mechanisms of behavioral change. Resulting research findings will inform prevention, practice, and policy, resulting in economic and societal benefits through improved quality of life for youths, their families, and their communities.

这篇介绍性的论文通过描述一种跨学科的神经科学方法来理解和拦截成瘾的发育途径，构建了成瘾神经科学特刊“物质使用的神经预防”。我们的综合模型来源于生物医学研究，为现有的和新的基于证据的预防策略的潜在机制提供了线索。为横切科学家“社区”提供的支持性转化研究基础设施指导这项工作，为干预措施的设计提供信息，这些干预措施更直接地针对我们旨在预防的现象的潜在产生者；即，不良的生物行为健康导致物质使用倾向增加，开始，升级和成瘾。推进这种方法以解决物质使用预防研究中的差距，包括确定共同点和优先事项，促进跨学科交流，分享病因学发现，应用多层次方法分析综合数据集，以及确定协作调查可以更好地理解行为改变机制的方法。由此产生的研究结果将为预防、实践和政策提供信息，通过改善青年及其家庭和社区的生活质量，产生经济和社会效益。

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引用次数: 0

Sex-specific effects of predator scent stress on fear, anxiety-like behavior and methamphetamine seeking in rats 捕食者气味压力对老鼠恐惧、焦虑样行为和甲基苯丙胺寻找的性别特异性影响

Addiction neuroscience

Pub Date : 2025-03-20 DOI: 10.1016/j.addicn.2025.100205

CG Modrak , CS Wilkinson , AD Claypool , AJ Moore , L Wu , LA Knackstedt , M Schwendt

Methamphetamine use disorder (MUD) is frequently comorbid with other disorders, such as post-traumatic stress disorder (PTSD). Here, we used a rat model of PTSD+MUD to evaluate the influence of sex and stress on methamphetamine-seeking and on the activation of frontocortical regions during reinstatement of meth‑seeking. Male and female Sprague-Dawley rats were exposed to predator scent stress (PSS) or a control odor for 10 min, followed by anxiety testing one week later. Rats were re-exposed to the odor context three weeks after the exposure and then self-administered methamphetamine for 18 days. Rats underwent extinction training followed by a cue-primed reinstatement test. We found evidence for sex-specific fear and anxiety-like behaviors in PSS-exposed rats, with females exhibiting anxiety-like behavior in the elevated plus maze and males exhibiting increased acoustic startle response. There were no effects of PSS on methamphetamine intake, but males exhibited greater intake and cued reinstatement. PSS-exposed females reinstated methamphetamine-seeking, but control-exposed females did not, in parallel with higher reinstatement-induced infralimbic cortex c-Fos expression. PSS males exhibited reduced prelimbic and infralimbic c-Fos relative to control-exposed males despite similar reinstatement behavior. To identify relationships between fear and anxiety-like behavior, cortical activation, and meth‑seeking, a principal components analysis was used. The analysis revealed that discrete behaviors exhibited during PSS exposure (locomotion and digging), together with select markers of anxiety (reduced startle response), predict methamphetamine intake and seeking. Altogether, these findings suggest that a specific set of stress-reactive and anxiety-like behaviors contribute to long-term resilience to drug-taking and seeking in a sex-specific manner.

甲基苯丙胺使用障碍（MUD）经常与创伤后应激障碍（PTSD）等其他疾病并发。在此，我们使用创伤后应激障碍+MUD大鼠模型来评估性别和应激对甲基苯丙胺寻求以及在甲基苯丙胺寻求恢复过程中对前皮质区域激活的影响。雄性和雌性 Sprague-Dawley 大鼠暴露于捕食者气味应激（PSS）或对照组气味 10 分钟，一周后进行焦虑测试。暴露三周后，大鼠再次暴露于气味环境，然后自我注射甲基苯丙胺 18 天。对大鼠进行消退训练，然后进行线索刺激恢复测试。我们发现，暴露于 PSS 的大鼠存在性别特异性恐惧和焦虑样行为，雌性大鼠在高架加迷宫中表现出焦虑样行为，雄性大鼠则表现出更高的声学惊吓反应。PSS 对甲基苯丙胺摄入量没有影响，但雄性表现出更大的摄入量和诱导恢复。暴露于 PSS 的雌性会恢复寻求甲基苯丙胺的行为，而暴露于对照组的雌性则不会，与此同时，恢复诱导的下边缘皮层 c-Fos 表达更高。与对照组暴露的雄性相比，尽管恢复行为相似，但PSS雄性的前边缘和下边缘c-Fos表达减少。为了确定恐惧和焦虑样行为、皮层激活和寻求甲基之间的关系，我们使用了主成分分析法。分析结果表明，暴露于 PSS 期间表现出的离散行为（运动和挖掘），连同选定的焦虑标记（惊吓反应降低），可预测甲基苯丙胺的摄入和寻求。总之，这些研究结果表明，一系列特定的应激反应和焦虑样行为以性别特异性的方式促进了对吸食和寻求毒品的长期适应能力。

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引用次数: 0

Multiple memory object-drug association task (MODAT) for the study of polydrug associations 多记忆客体-药物关联任务（MODAT）用于研究多药物关联

Addiction neuroscience

Pub Date : 2025-02-22 DOI: 10.1016/j.addicn.2025.100204

Madalyn Hafenbreidel , Thomas Vaissiere , Erica J Young , Meghana Arza , Cadence Fisher , Gavin Rumbaugh , Courtney A. Miller

Polysubstance use is common among individuals with substance use disorder (SUD). However, the underlying neurobiology of the complex interactions between different drug classes is understudied. Further, drug associations can serve as relapse factors, but current behavioral paradigms commonly used to assess these learned associations are not as easily adapted to administration of multiple drugs. To address this, we developed the multiple memory object-drug association task (MODAT), an object-based associative memory task that allows for the same mouse to learn to associate different objects with different drugs. Four neutral scents were identified, as were four objects that could still be discriminated between after a delay. These were then combined to create four complex object-scent stimuli equally preferred by mice. Using these compound stimuli, we optimized MODAT using a stimulant (methamphetamine [METH]) and an opioid (heroin [HER]). Under the optimized protocol conditions, mice increased locomotion upon presentation of a stimulus paired with METH or HER, but not saline, during retention testing. Moreover, mice spent more time investigating the HER-, but not METH-paired stimulus. This provided two distinct behavioral readouts for assessing drug-associated memory in the same animals. A broad survey of cFos expression in the brain was performed to identify brain regions differentially activated between METH and HER-associated memory retrieval. Interestingly, many brain regions displayed decreased activation with HER-associated memory retrieval relative to METH. These regions included the prelimbic and infralimbic cortices and the nucleus accumbens. The converse was true for regions such as the lateral habenula and hypothalamus. MODAT presents a novel and easily implemented paradigm that requires no special equipment to examine multiple drug-associated memories in the same mouse as a way to examine the neurobiology of polysubstance exposure.

多种物质使用在物质使用障碍（SUD）患者中很常见。然而，不同药物之间复杂相互作用的潜在神经生物学尚未得到充分研究。此外，药物关联可以作为复发因素，但目前通常用于评估这些习得性关联的行为范式并不容易适应多种药物的施用。为了解决这个问题，我们开发了多重记忆对象-药物关联任务（MODAT），这是一种基于对象的联想记忆任务，允许同一只老鼠学习将不同的对象与不同的药物联系起来。四种中性气味被识别出来，四种物体在一段时间后仍然可以被区分出来。然后将它们结合起来，创造出四种复杂的物体气味刺激，老鼠都喜欢这种刺激。使用这些复合刺激，我们使用兴奋剂（甲基苯丙胺[冰毒]）和阿片类药物（海洛因[HER]）来优化MODAT。在优化的方案条件下，小鼠在保留测试中，在刺激与冰毒或HER配对时增加运动，而不是生理盐水。此外，小鼠花更多的时间研究HER-配对刺激，而不是冰毒配对刺激。这为评估同一只动物的药物相关记忆提供了两种不同的行为读数。对cFos在大脑中的表达进行了广泛的调查，以确定在甲基苯丙胺和her相关记忆检索之间激活的大脑区域的差异。有趣的是，与甲基安非他明相比，许多大脑区域显示her相关记忆检索的激活减少。这些区域包括边缘前皮层、边缘下皮层和伏隔核。相反的情况也适用于外侧链和下丘脑等区域。MODAT提供了一种新颖且易于实现的范式，不需要特殊设备就可以在同一只小鼠中检查多种药物相关记忆，作为一种检查多物质暴露的神经生物学的方法。

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引用次数: 0

Endogenous regulator of G protein signaling 14 (RGS14) blunts cocaine-induced emotionally motivated behaviors in female mice 内源性G蛋白信号14调节因子（RGS14）减弱可卡因诱导的雌性小鼠情绪动机行为

Addiction neuroscience

Pub Date : 2025-02-15 DOI: 10.1016/j.addicn.2025.100203

Sara N. Bramlett , Stephanie L. Foster , David Weinshenker , John R. Hepler

Addictive drugs hijack the neuronal mechanisms of learning and memory in motivation and emotion processing circuits to reinforce their own use. Regulator of G-protein Signaling 14 (RGS14) is a natural suppressor of post-synaptic plasticity underlying learning and memory in the hippocampus. The present study used immunofluorescence and RGS14 knockout mice to assess the role of RGS14 in behavioral plasticity and reward learning induced by chronic cocaine in emotional-motivational pathways. We report that RGS14 is strongly expressed in discrete regions of the ventral striatum and extended amygdala in wild-type mice, and is co-expressed with D1 and D2 dopamine receptors in neurons of the nucleus accumbens. Of note, we found that RGS14 is upregulated in the nucleus accumbens following acute cocaine treatment in mice with chronic cocaine history. We found significantly increased cocaine-induced locomotor sensitization, as well as enhanced conditioned place preference and conditioned locomotor activity in RGS14-deficient mice compared to wild-type littermates. Together, these findings suggest that endogenous RGS14 suppresses cocaine-induced plasticity in emotional-motivational pathways, implicating RGS14 as a protective agent against the maladaptive neuroplastic changes that occur during addiction.

成瘾性药物劫持了动机和情绪处理回路中学习和记忆的神经元机制，以强化其自身的使用。G蛋白信号调节器14（RGS14）是海马学习和记忆中突触后可塑性的天然抑制因子。本研究利用免疫荧光和 RGS14 基因敲除小鼠来评估 RGS14 在行为可塑性和可卡因诱导的奖赏学习中的作用。我们报告说，RGS14 在野生型小鼠腹侧纹状体和扩展杏仁核的离散区域中强表达，并与 D1 和 D2 多巴胺受体共同表达于腔核神经元中。值得注意的是，我们发现在对有慢性可卡因史的小鼠进行急性可卡因治疗后，RGS14 在累加核中上调。我们发现，与野生型小鼠相比，RGS14缺陷小鼠体内可卡因诱导的运动敏感性明显增加，条件性位置偏好和条件性运动活动也有所增强。这些发现共同表明，内源性 RGS14 可抑制可卡因诱导的情绪-动机通路的可塑性，从而使 RGS14 成为一种保护剂，防止成瘾过程中出现的神经可塑性不良变化。

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引用次数: 0

Presence of distinct operant phenotypes and transient withdrawal-induced escalation of operant ethanol intake in female rats 在雌性大鼠中存在不同的操作性表型和短暂戒断诱导的操作性乙醇摄入量增加

Addiction neuroscience

Pub Date : 2025-01-30 DOI: 10.1016/j.addicn.2025.100198

Joseph R Pitock, Shannon R Wheeler, Arleen Perez Ayala, Shikun Hou, Nathaly M Arce Soto, Elizabeth J Glover

Operant self-administration is frequently used to investigate the neurobiological mechanisms underlying alcohol seeking and drinking and to evaluate treatments of alcohol use disorder (AUD). Although widely used by the research community, there is a paucity of operant ethanol self-administration studies that include female subjects. The current study characterizes home cage drinking and operant ethanol self-administration in female Sprague Dawley, Long Evans, and Wistar rats. Rats underwent three weeks of intermittent-access two-bottle choice home cage drinking before being trained to lever press for ethanol in standard operant chambers equipped with contact lickometers. After capturing baseline operant performance, rats were chronically exposed to control or ethanol liquid diet using the Lieber-DeCarli method followed by re-evaluation of operant performance during acute withdrawal. Our findings reveal the presence of three distinct operant phenotypes, the prevalence of which within each strain is strikingly similar to our previous observations in males. Within a given phenotype, rats of each strain performed similarly during operant testing. Ethanol intake during home cage drinking was unable to predict future operant phenotype. Relative to controls, Drinkers chronically exposed to ethanol liquid diet exhibited a significant, but transient, escalation in consummatory, but not appetitive, responding during acute withdrawal. Collectively, these data closely parallel many of our previous observations in males while also highlighting potential sex differences in drinking strategies following dependence. Our findings provide new insight into similarities and differences in operant ethanol self-administration between males and females and emphasize the importance of including females in future studies of ethanol drinking and dependence.

操作性自我给药经常被用来研究酒精寻求和饮酒的神经生物学机制，并评估酒精使用障碍（AUD）的治疗方法。尽管被研究界广泛使用，但缺乏包括女性受试者的操作性乙醇自我给药研究。目前的研究以雌性Sprague Dawley大鼠、Long Evans大鼠和Wistar大鼠为研究对象，对其进行了家庭笼饮水和操作性乙醇自我给药。在训练大鼠在配备接触式液滴计的标准操作室中杠杆按压乙醇之前，大鼠进行了为期三周的间歇访问两瓶选择家庭笼饮水。在捕获基线操作性能后，采用Lieber-DeCarli方法将大鼠长期暴露于对照或乙醇液体饮食中，然后在急性戒断期间重新评估操作性能。我们的研究结果揭示了三种不同的操作表型的存在，每种菌株的患病率与我们之前在男性中的观察结果惊人地相似。在给定表型内，每个菌株的大鼠在操作性测试中表现相似。家庭笼饮期间的乙醇摄入量无法预测未来的操作表型。与对照组相比，长期暴露于乙醇液体饮食的饮酒者在急性戒断期间表现出显著的，但短暂的，促终性上升，而不是食欲上升。总的来说，这些数据与我们之前对男性的观察结果非常相似，同时也强调了依赖后饮酒策略的潜在性别差异。我们的研究结果为男性和女性在操作性乙醇自我管理方面的异同提供了新的见解，并强调了在未来的乙醇饮用和依赖研究中纳入女性的重要性。

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引用次数: 0

Biotin's protective effects against nicotine withdrawal-induced anxiety and depression: Mechanistic insights into serotonin, inflammation, BDNF, and oxidative stress in male rats 生物素对尼古丁戒断引起的焦虑和抑郁的保护作用：对雄性大鼠血清素、炎症、BDNF和氧化应激的机制见解

Addiction neuroscience

Pub Date : 2025-01-23 DOI: 10.1016/j.addicn.2025.100199

Dawood Hossaini , Mohammad Jalal Nazari , Khan Baba Ghazanfar , Mohammad Edris Amiri , Mohammad Tariq Anwary , Mohammad Jawad Jawad , Murtaza Haidary

Introduction

Substance use disorders, particularly nicotine use disorders, represent a significant public health problem, with adolescents particularly vulnerable to their adverse effects. This study examined the potential anxiolytic and antidepressant effects of biotin in attenuating the behavioral and neurobiological changes associated with nicotine withdrawal in adolescent rats.

Materials and Methods

Sixty male Sprague-Dawley rats were subjected to nicotine administration and subsequently, nicotine withdrawal, after which behavioral assessments included the open-field test, the elevated plus-maze test, and the forced-swimming test performed after withdrawal to assess anxiety and depression behaviors. We also performed biochemical analyses to measure serotonin levels, monoamine oxidase A activity, brain neurotrophic factor concentration, and markers of oxidative stress.

Results

The results demonstrated that nicotine withdrawal intensifies behavioral symptoms of anxiety and depression by disrupting serotonin metabolism, triggering inflammatory responses, and upsetting the balance of oxidative stress. Treatment with biotin, particularly at higher doses, significantly alleviated these withdrawal-induced behavioral changes. Mechanistically, biotin was found to increase serotonin levels and decrease monoamine oxidase Activity, elevate brain-derived neurotrophic factor levels, reduce glial fibrillary acidic protein expression, and improve oxidative stress balance within the cortical tissue.

Discussion

This study suggests that biotin may have significant therapeutic potential for alleviating the side effects associated with nicotine withdrawal, particularly anxiety and depression. Given the complex neurobiological mechanisms underlying withdrawal symptoms, biotin's ability to modulate critical signaling pathways such as serotonin metabolism, neuroinflammation, and oxidative stress could provide a multifaceted treatment approach.

物质使用障碍，特别是尼古丁使用障碍，是一个重大的公共卫生问题，青少年特别容易受到其不利影响。本研究探讨了生物素在减轻青春期大鼠尼古丁戒断相关的行为和神经生物学变化方面的潜在抗焦虑和抗抑郁作用。材料与方法雄性Sprague-Dawley大鼠60只，先给药，然后戒断尼古丁，戒断后进行行为学评估，包括开放场测试、升高+迷宫测试和戒断后的强迫游泳测试，评估焦虑和抑郁行为。我们还进行了生化分析，测量血清素水平、单胺氧化酶A活性、脑神经营养因子浓度和氧化应激标志物。结果尼古丁戒断通过扰乱血清素代谢、引发炎症反应和破坏氧化应激平衡，加重了焦虑和抑郁行为症状。用生物素治疗，特别是高剂量治疗，可显著减轻这些戒断引起的行为改变。机制上，生物素可提高血清素水平，降低单胺氧化酶活性，提高脑源性神经营养因子水平，降低胶质纤维酸性蛋白表达，改善皮质组织内氧化应激平衡。本研究表明，生物素可能具有显著的治疗潜力，可以减轻与尼古丁戒断相关的副作用，特别是焦虑和抑郁。考虑到戒断症状背后复杂的神经生物学机制，生物素调节关键信号通路（如血清素代谢、神经炎症和氧化应激）的能力可以提供多方面的治疗方法。

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引用次数: 0