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Evaluating the impact of concurrent sucrose availability on operant ethanol self-administration in male and female Long Evans rats 评估同时蔗糖可用量对雄性和雌性Long Evans大鼠操作性乙醇自我给药的影响
Pub Date : 2025-01-18 DOI: 10.1016/j.addicn.2025.100196
Olivia A. Ortelli, Jeffrey L. Weiner
Investigating how environmental factors, such as the availability of non-ethanol alternative reinforcers, influences ethanol self-administration is critical for understanding the pathology of alcohol use disorder (AUD). Here we established the first operant choice paradigm that leverages the strengths of the sipper tube self-administration model to investigate how concurrent access to sucrose altered ethanol self-administration in male and female Long Evans rats. Choice behavior was examined using two distinct paradigms, including a novel adaptation of the response requirement paradigm. Under both a fixed-ratio or response requirement paradigm, we observed that concurrent availability of an alternative reinforcer significantly reduced appetitive and consummatory ethanol drinking-related behaviors. Furthermore, we assessed the sensitivity of the response requirement choice paradigm by administering the pharmacological stressor yohimbine and by altering the taste of the ethanol solution. Yohimbine administration non-selectively increased ethanol and sucrose intake, but not seeking, while taste adulteration decreased ethanol seeking and intake. These experiments demonstrate the utility of two concurrent choice paradigms that can more accurately capture AUD-like phenotypes, such as ethanol-directed choice in the face of alternative reinforcers. Future studies should investigate how models of vulnerability and dependence alter ethanol choice behavior under these paradigms.
研究环境因素(如非乙醇替代强化剂的可用性)如何影响乙醇自我给药,对于理解酒精使用障碍(AUD)的病理至关重要。在这里,我们建立了第一个操作性选择范式,利用吸管自我给药模型的优势来研究同时获得蔗糖如何改变雄性和雌性朗埃文斯大鼠的乙醇自我给药。选择行为采用两种不同的范式进行研究,其中包括一种对反应要求范式的新适应。在固定比例或反应要求范式下,我们观察到可选择强化物的同时可用性显著降低了食欲和完成性乙醇饮酒相关行为。此外,我们通过给予育亨宾药理学应激源和改变乙醇溶液的味道来评估反应要求选择范式的敏感性。育亨宾非选择性地增加了乙醇和蔗糖的摄入量,但没有增加寻求量,而味道掺假减少了乙醇的寻求和摄入量。这些实验证明了两种并发选择范式的效用,它们可以更准确地捕获aud样表型,例如面对替代强化物时的乙醇导向选择。未来的研究应探讨脆弱性和依赖性模型如何在这些范式下改变乙醇选择行为。
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引用次数: 0
Oxytocin attenuates demand for cocaine in female rats 催产素降低了雌性大鼠对可卡因的需求
Pub Date : 2025-01-15 DOI: 10.1016/j.addicn.2025.100197
Amy S. Kohtz , Hannah Davies , Belle Lin , Gary Aston-Jones
There are substantial sex differences in substance use disorders (SUDs), and a key feature of SUD is pathologically high economic demand for drug. The hypothalamic neuropeptide oxytocin (OXT) is heavily implicated in the modern treatment of SUDs. Using a within-session threshold behavioral economics (BE) procedure, we quantified demand elasticity (a, inverse motivation) and free consumption (Q0) in male and female rats to investigate the effect of OXT on cocaine demand. Results showed that OXT decreased motivation for cocaine; an effect greater during the high-demand phase (diestrus, low progesterone, P4) vs low demand phases (proestrus, high P4). We confirmed our prior findings that P4 attenuates cocaine demand in female rats and that chronic cocaine self-administration disrupts estrus cyclicity. Following each injection, OXT at either 0.1mg/kg or 0.3mg/kg restored estrous cycling in intact females with prior cocaine experience for one week and remained effective with up to 4 weeks of injections. Fos reactivity in OXT+ neurons was greater when rats were in proestrus compared to diestrus and significantly correlated to motivation and circulating levels of P4. Finally, using ovariectomized females with P4 replacement, we show that P4’s demand attenuating effects are reversed by atosiban (1.0 mg/kg, IP), an OXT antagonist. These data show an interaction between oxytocin and progesterone in female rats that may underlie differences in cocaine demand between sexes. Additionally, we show critical periods for using OXT as a treatment to reduce cocaine demand in females. Our results indicate novel therapeutic treatments for SUDs must be tailored to hormonal states.
物质使用障碍(SUD)存在明显的性别差异,其一个关键特征是病理性的高经济药物需求。下丘脑神经肽催产素(OXT)与sud的现代治疗密切相关。利用会话内阈值行为经济学(BE)方法,我们量化了雄性和雌性大鼠的需求弹性(a,逆动机)和自由消费(Q0),以研究OXT对可卡因需求的影响。结果表明,氧化氧疗法降低了可卡因的使用动机;在高需求期(发情期,低黄体酮,P4)比低需求期(发情期,高P4)的影响更大。我们证实了我们之前的发现,P4降低了雌性大鼠对可卡因的需求,慢性可卡因自我给药破坏了发情周期。每次注射后,0.1mg/kg或0.3mg/kg的OXT可使先前有可卡因经验的完整雌性恢复一周的发情周期,并在注射后4周保持有效。大鼠处于发情期时,OXT+神经元中的Fos反应性比处于发情期时更强,并且与动机和循环P4水平显著相关。最后,在切除卵巢并置换P4的雌性小鼠中,研究人员发现,OXT拮抗剂阿托西班(1.0 mg/kg, IP)逆转了P4的需求衰减作用。这些数据表明,雌性大鼠体内的催产素和黄体酮之间存在相互作用,这可能是两性对可卡因需求差异的基础。此外,我们展示了使用OXT作为治疗减少女性可卡因需求的关键时期。我们的研究结果表明,治疗sud的新方法必须根据激素状态量身定制。
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引用次数: 0
Concurrent and prospective relations between aberrant stress-induced frontal alpha asymmetry and cannabis use disorder 异常应激诱导的额叶α不对称与大麻使用障碍的同时和未来关系
Pub Date : 2025-01-09 DOI: 10.1016/j.addicn.2025.100195
Brandon S. Schermitzler , Julia Y. Gorday , Michael Griffin , Richard J. Macatee

Background

Cannabis Use Disorder (CUD) is prevalent and associated with significant disability. Stress potentiation of drug use motivation is a mechanism implicated in CUD; however, little is known about the neurobiological mechanisms through which stress impacts cannabis use motivation. Frontal alpha asymmetry (FAA), an index of approach motivation, is sensitive to acute stress, so this study sought to examine the relationship between stress-potentiated FAA and cannabis-related problems.

Method

Non-treatment-seeking regular cannabis users in a stress task study (N = 102) and a control task study (N = 52) completed a resting state task with concurrent electroencephalogram recording before and after a stressor or control task. Changes in FAA from pre- to post-task represented a neurophysiological index of approach motivation change. Participants completed self-report and clinician-assessed measures of cannabis-related problems. Participants in the stress study re-completed all study components three months later.

Results

Relative to the control study, participants in the stress study showed a greater shift from right to left alpha-band power at frontal sites. More cannabis-related problems, but not past-month cannabis use sessions, correlated with a blunted stress-induced FAA response, which predicted greater maintenance of cannabis-related problems three months later. Baseline cannabis-related problems were not associated with changes in the stress-induced FAA response from baseline to follow-up, and changes in cannabis-related problems across the three-month study period were not associated with changes in the stress-induced FAA response. The stress-induced FAA response demonstrated good stability over three months.

Conclusion

The stress-induced FAA response may represent a stable predictor of cannabis-related problems and may have implications for clinical practice.
大麻使用障碍(CUD)很普遍,并与严重的残疾有关。药物使用动机的应激增强机制与CUD有关;然而,人们对压力影响大麻使用动机的神经生物学机制知之甚少。额叶α不对称(FAA)是一种接近动机指标,对急性应激敏感,因此本研究旨在探讨应激增强的FAA与大麻相关问题之间的关系。方法在应激任务研究(N = 102)和对照任务研究(N = 52)中,非寻求治疗的常规大麻使用者在应激或对照任务前后完成静息状态任务,并发记录脑电图。从任务前到任务后,FAA的变化代表了接近动机变化的神经生理指标。参与者完成了大麻相关问题的自我报告和临床评估措施。压力研究的参与者在三个月后重新完成了所有的研究内容。结果:与对照研究相比,在压力研究中,参与者的额部α波段功率从右到左的变化更大。更多的大麻相关问题,而不是过去一个月的大麻使用时间,与压力诱导的FAA反应迟钝相关,这预示着三个月后大麻相关问题的维持程度更高。基线大麻相关问题与从基线到随访期间应激诱导的FAA反应的变化无关,并且在三个月的研究期间,大麻相关问题的变化与应激诱导的FAA反应的变化无关。应力诱导的FAA反应在三个月内表现出良好的稳定性。结论应激诱导的FAA反应可能是大麻相关问题的稳定预测因子,并可能对临床实践具有指导意义。
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引用次数: 0
Central amygdala neuroimmune signaling in alcohol use disorder 酒精使用障碍中的中央杏仁核神经免疫信号
Pub Date : 2024-12-21 DOI: 10.1016/j.addicn.2024.100194
Mariam Melkumyan , Patrick A. Randall , Yuval Silberman
Alcohol Use Disorder (AUD) is a prevalent and debilitating condition characterized by an inability to control alcohol consumption despite adverse consequences. Current treatments for AUD, including FDA-approved medications such as naltrexone and acamprosate, have limited efficacy and compliance, underscoring the need for novel therapeutic approaches. The central amygdala (CeA) plays a crucial role in the development and maintenance of AUD, particularly aspects associated with stress and binge behaviors. Recent research indicates neuroimmune signaling in the CeA is emerging as a key factor in this process. Chronic alcohol consumption disrupts neuroimmune signaling, leading to altered cytokine expression and activation of glial cells, including astrocytes and microglia. These changes contribute to the dysregulation of neural circuits involved in reward and stress, perpetuating alcohol-seeking behavior and relapse. This review delves into how chronic alcohol exposure affects neuroimmune signaling in the CeA, contributing to the pathophysiology of AUD. By focusing on the impact of cytokine expression and glial cell activation, this review aims to elucidate the mechanisms by which neuroinflammation in the CeA influences alcohol-related behaviors. By providing a comprehensive overview of the current state of research, this review identifies potential therapeutic targets for AUD. Understanding the complex interplay between neuroimmune signaling and alcohol-related behaviors may pave the way for more effective treatments and improved outcomes for individuals struggling with AUD.
酒精使用障碍(AUD)是一种普遍和衰弱的状况,其特征是尽管有不良后果,但仍无法控制酒精消费。目前治疗AUD的方法,包括fda批准的药物,如纳曲酮和阿坎普罗酸,疗效和依从性有限,强调需要新的治疗方法。中央杏仁核(CeA)在AUD的发展和维持中起着至关重要的作用,特别是与压力和暴食行为相关的方面。最近的研究表明,CeA中的神经免疫信号是这一过程的关键因素。长期饮酒破坏神经免疫信号,导致细胞因子表达改变和胶质细胞活化,包括星形胶质细胞和小胶质细胞。这些变化导致与奖励和压力有关的神经回路失调,使寻求酒精的行为永久化并复发。这篇综述深入探讨了慢性酒精暴露如何影响CeA中的神经免疫信号,促进AUD的病理生理。通过对细胞因子表达和神经胶质细胞活化的影响,本文旨在阐明CeA中神经炎症影响酒精相关行为的机制。通过对当前研究状况的全面概述,本综述确定了AUD的潜在治疗靶点。了解神经免疫信号和酒精相关行为之间复杂的相互作用可能为更有效的治疗铺平道路,并改善患有AUD的个体的预后。
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引用次数: 0
Corrigendum to “Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta” [Addiction Neuroscience 13 (2024) 100183] “神经递质定义的细胞类型在腹侧被盖区和黑质致密部的比例和分布”的更正[成瘾神经科学13 (2024)100183]
Pub Date : 2024-12-13 DOI: 10.1016/j.addicn.2024.100193
William S. Conrad , Lucie Oriol , Grace J. Kollman , Lauren Faget , Thomas S. Hnasko
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引用次数: 0
Neuronal heterogeneity in the ventral tegmental area: Distinct contributions to reward circuitry and motivated behavior 腹侧被盖区的神经元异质性:对奖赏回路和动机行为的独特贡献
Pub Date : 2024-11-28 DOI: 10.1016/j.addicn.2024.100191
N. Dalton Fitzgerald, Jeremy J. Day
The ventral tegmental area (VTA) is a critical component of brain reward circuitry that influences motivation, learning, and emotional regulation. Although this role was traditionally attributed primarily to VTA dopamine (DA) neurons, recent advances in transcriptomics and intersectional genetics have revealed significant cell type heterogeneity within the VTA, challenging these established notions. Distinct subtypes of DA neurons can be identified across the VTA and substantia nigra pars compacta (SNc) by characteristics that include gene expression patterns (molecular identity), connectivity motifs (network identity), and patterns of task-linked activity and neurotransmitter release (computational identity). This review aims to synthesize current knowledge of diverse neuronal populations in the VTA, including distinct subtypes of DA, glutamate (GLUT), and GABAergic neurons and combinatorial cells alongside well-characterized markers of these neuronal subclasses. Furthermore, this review highlights known projection targets and the role of diverse VTA cell types in motivated behavior. Finally, we highlight emerging intersectional techniques that enable targeted studies of the vast array of cell types and discuss areas of research important for the future direction of the field. Understanding VTA cell type heterogeneity may yield new insights into the reward system, offering potential avenues for treating substance use disorders and other related conditions.
腹侧被盖区(VTA)是影响动机、学习和情绪调节的大脑奖励回路的关键组成部分。虽然这一作用传统上主要归因于VTA多巴胺(DA)神经元,但转录组学和交叉遗传学的最新进展揭示了VTA内显著的细胞类型异质性,挑战了这些既定的观念。通过基因表达模式(分子同一性)、连接基元(网络同一性)、任务相关活动模式和神经递质释放模式(计算同一性)等特征,可以在VTA和黑质致密部(SNc)中识别出不同的DA神经元亚型。本综述旨在综合目前对VTA中不同神经元群的了解,包括DA、谷氨酸(GLUT)和gaba能神经元的不同亚型,以及这些神经元亚类的组合细胞。此外,本综述强调了已知的投射靶点和不同VTA细胞类型在动机行为中的作用。最后,我们强调了新兴的交叉技术,这些技术能够对大量细胞类型进行有针对性的研究,并讨论了对该领域未来方向重要的研究领域。了解VTA细胞类型的异质性可能会对奖励系统产生新的见解,为治疗物质使用障碍和其他相关疾病提供潜在的途径。
{"title":"Neuronal heterogeneity in the ventral tegmental area: Distinct contributions to reward circuitry and motivated behavior","authors":"N. Dalton Fitzgerald,&nbsp;Jeremy J. Day","doi":"10.1016/j.addicn.2024.100191","DOIUrl":"10.1016/j.addicn.2024.100191","url":null,"abstract":"<div><div>The ventral tegmental area (VTA) is a critical component of brain reward circuitry that influences motivation, learning, and emotional regulation. Although this role was traditionally attributed primarily to VTA dopamine (DA) neurons, recent advances in transcriptomics and intersectional genetics have revealed significant cell type heterogeneity within the VTA, challenging these established notions. Distinct subtypes of DA neurons can be identified across the VTA and substantia nigra pars compacta (SNc) by characteristics that include gene expression patterns (molecular identity), connectivity motifs (network identity), and patterns of task-linked activity and neurotransmitter release (computational identity). This review aims to synthesize current knowledge of diverse neuronal populations in the VTA, including distinct subtypes of DA, glutamate (GLUT), and GABAergic neurons and combinatorial cells alongside well-characterized markers of these neuronal subclasses. Furthermore, this review highlights known projection targets and the role of diverse VTA cell types in motivated behavior. Finally, we highlight emerging intersectional techniques that enable targeted studies of the vast array of cell types and discuss areas of research important for the future direction of the field. Understanding VTA cell type heterogeneity may yield new insights into the reward system, offering potential avenues for treating substance use disorders and other related conditions.</div></div>","PeriodicalId":72067,"journal":{"name":"Addiction neuroscience","volume":"14 ","pages":"Article 100191"},"PeriodicalIF":0.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143169128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Potential roles for vitamin D in preventing and treating impulse control disorders, behavioral addictions, and substance use disorders: A scoping review 维生素D在预防和治疗冲动控制障碍、行为成瘾和物质使用障碍中的潜在作用:范围综述
Pub Date : 2024-11-26 DOI: 10.1016/j.addicn.2024.100190
Laya Jalilian-Khave , Razi Kitaneh , Binah Baht Ysrayl , Anna Borelli , Melissa C. Funaro , Marc N. Potenza , Gustavo A. Angarita
Vitamin D deficiency is a problem of endemic proportions. Vitamin D is a major regulator of dopaminergic and serotonergic circuits, pathways implicated in addictive disorders. This scoping review (OSF registered as 67yhb) examines preclinical and clinical studies exploring relationships between vitamin D in impulse control disorders, behavioral addictions, and substance use disorders. We searched Ovid MEDLINE, Embase, APA PsycInfo, Cochrane Library, Web of Science, and Scopus databases. We extracted and summarized quantitative and qualitative data through a narrative synthesis and assessed the quality of studies using the Joanna Briggs Institute (JBI) and SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) criteria. Of 5,442 initial records identified, 28 preclinical and clinical studies were included. For most conditions, we found a negative relationship between vitamin D levels and symptom presence and/or severity. While data suggest a potential beneficial effect of vitamin D on preventing or treating these conditions, there were significant limitations identified by the JBI and SYRCLE assessments. Future studies should include impulse control disorders and other under-explored conditions, address heterogeneity regarding forms, doses, and duration of exposures to vitamin D, and explore vitamin D's potential therapeutic mechanisms.
维生素D缺乏是一个地方性的问题。维生素D是多巴胺能和血清素能回路的主要调节剂,与成瘾性疾病有关。本综述(OSF注册号为67yhb)检查了临床前和临床研究,探讨了维生素D在冲动控制障碍、行为成瘾和物质使用障碍中的关系。我们检索了Ovid MEDLINE、Embase、APA PsycInfo、Cochrane Library、Web of Science和Scopus数据库。我们通过叙述性综合提取和总结定量和定性数据,并使用乔安娜布里格斯研究所(JBI)和sycle(实验动物实验系统审查中心)标准评估研究质量。在确定的5442份初始记录中,包括28份临床前和临床研究。在大多数情况下,我们发现维生素D水平与症状存在和/或严重程度呈负相关。虽然数据表明维生素D对预防或治疗这些疾病有潜在的有益作用,但JBI和sycle评估发现了显著的局限性。未来的研究应该包括冲动控制障碍和其他未被探索的条件,解决维生素D的形式、剂量和暴露时间的异质性,并探索维生素D的潜在治疗机制。
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引用次数: 0
Serotonin circuits act cooperatively with pathophysiology of opioid use disorder 5 -羟色胺回路与阿片类药物使用障碍的病理生理协同作用
Pub Date : 2024-11-24 DOI: 10.1016/j.addicn.2024.100187
Arakawa Hiroyuki , Ozawa Akihiko
Opioid abuse and its negative effect have become a critical epidemic, putting our health and society in jeopardy. Opioids are effective treatment for pain, but at risk for developing associated health threatening impacts including the euphoria associated relapsing effects, persistent occurrence with addictive and withdrawal symptoms, and consequent respiratory depression and apnea. The opioid use disorder (OUD), represented as those recurring phases of symptoms, is initiated with mediation of opioid receptor signaling pathway and subsequent neurocircuitry transformation with homeostatic and motivational change. It has been imperative to establish modulatory mechanisms and alternative treatments to mitigate OUD. This review deals with central serotonin (5-HT) system as a cooperative mediator with OUD-related neural processing. We briefly introduce molecular base of opioid receptors and available research tools in mouse models and examine OUD-phase dependent circuit mechanisms, including pain, addiction, and respiratory depression. We interrogate the potential neural roles of 5-HT in OUD-related symptoms including 5-HT toxicity and pathophysiology and discuss potential availability of 5-HT-related agents as a neuromodulatory therapeutic interacting with opioid mediated neural mechanisms and the OUD-related symptoms.
阿片类药物滥用及其负面影响已成为一种严重的流行病,使我们的健康和社会处于危险之中。阿片类药物是治疗疼痛的有效药物,但存在产生相关健康威胁影响的风险,包括欣快感相关的复发效应,持续出现成瘾和戒断症状,以及随之而来的呼吸抑制和呼吸暂停。阿片类药物使用障碍(OUD)表现为症状反复出现的阶段,是由阿片受体信号通路介导和随后的神经回路转化引起的,伴有稳态和动机变化。建立缓解OUD的调节机制和替代疗法已成为当务之急。本文综述了中枢5-羟色胺(5-HT)系统在oud相关神经处理中的协同调节作用。我们简要介绍了阿片受体的分子基础和小鼠模型中可用的研究工具,并检查了OUD-phase依赖回路机制,包括疼痛,成瘾和呼吸抑制。我们探讨了5-HT在oud相关症状中的潜在神经作用,包括5-HT毒性和病理生理,并讨论了5-HT相关药物作为与阿片介导的神经机制和oud相关症状相互作用的神经调节治疗的潜在可用性。
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引用次数: 0
Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition 巴甫洛夫线索诱发的酒精寻求会受到腹侧苍白球抑制的干扰
Pub Date : 2024-11-09 DOI: 10.1016/j.addicn.2024.100186
Jocelyn M. Richard , Bailey Newell , Preethi Muruganandan , Patricia H. Janak , Benjamin T. Saunders
Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50 % of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.
与酒精配对的线索会强烈刺激人们对酒精的渴望、寻求、消费和复吸。虽然腹侧苍白球与多种奖赏和行为类型的食欲和消费反应有关,但它在巴甫洛夫酒精线索行为反应中的作用以前尚未确定。在这里,我们测试了光遗传学抑制腹侧苍白球对雄性长伊文大鼠巴甫洛夫条件反射觅酒行为的影响。大鼠接受了巴甫洛夫条件反射,听觉提示是将酒精送到奖励口,而对照提示是不送酒精,直到大鼠在酒精提示时进入奖励口的次数持续多于对照提示。然后,我们测试了在 50% 的提示呈现过程中光遗传抑制的会话内效应。我们发现,在酒精线索期间对腹侧苍白球进行光遗传学抑制会降低进入奖励口的可能性和在奖励口停留的时间,并增加进入奖励口的潜伏期。总之,这些结果表明,正常的腹侧苍白球活动是巴甫洛夫酒精觅食的必要条件。
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引用次数: 0
Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents 神经紧张素受体 1 的偏向异构调节剂可减少啮齿动物的乙醇饮酒量和对乙醇给药的反应
Pub Date : 2024-11-02 DOI: 10.1016/j.addicn.2024.100185
Graydon B. Gereau , Diana Zhou , Kalynn Van Voorhies , Ryan E. Tyler , Jeffrey Campbell , Jackson G. Murray , Ali Alvarez-Pamir , Luke A. Wykoff , Michel A. Companion , Michael R. Jackson , Steven H. Olson , Lawrence S. Barak , Lauren M. Slosky , Ryan P. Vetreno , Joyce Besheer , Zoe A. McElligott
Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death [1]. Despite this, there are currently only 3 FDA approved pharmacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.
酒精使用障碍(AUDs)给社会和经济造成了巨大负担,在全球范围内,酒精滥用是导致过早死亡的第七大原因[1]。尽管如此,目前在美国只有 3 种经 FDA 批准的药物可用于治疗 AUDs。神经紧张素(Nts)系统长期以来一直被认为与调节与酒精滥用相关的行为有关。最近,一种新型化合物 SBI-553 在使用精神兴奋剂的临床前模型中显示出了良好的前景,该化合物可偏向于激活 Nts 受体 1(NTSR1)的作用。在这里,我们通过评估乙醇消耗、对乙醇的行为反应、对乙醇的生理敏感性和乙醇代谢的一系列综合实验,研究这种化合物改变乙醇介导的行为的功效。此外,我们还调查了回避和认知实验中的行为,以监测 SBI-553 的潜在副作用。我们发现,SBI-553 可降低小鼠的乙醇消耗量,但不会改变回避行为或新物体识别。我们还观察到小鼠对连续注射乙醇的生理反应存在性别差异。在大鼠体内,我们发现 SBI-553 可降低对乙醇间感觉效应的敏感性(使用巴甫洛夫药物辨别任务)。我们的数据表明,以 NTSR1 信号传导为靶点可能有望减轻酒精滥用,这也是对大量文献的补充,这些文献表明 NTSR1 可能是涉及多种强化物质精神作用的共同下游靶点。
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引用次数: 0
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Addiction neuroscience
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