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Assessment of reduction in stimulus generalization of ethanol-seeking during recovery: A rapid procedure 评估恢复期乙醇觅食刺激泛化的减少:快速程序。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-01 DOI: 10.1016/j.alcohol.2024.09.003
Previously, we developed a procedure which showed that longer histories of reinforced alternative behavior decrease the risk of relapse caused by a range of stimuli which had previously occasioned drinking. The decrease in relapse risk was likely due to a decrease in attention to the stimuli over the course of repeated engagement in the alternative behavior. However, this previous procedure was time consuming and did not mirror the procedure we used to observe changes in relapse risk. This study aimed at replicating the previous relationship between the duration of engaging in an alternative behavior and shift in stimulus generalization for drinking using a procedure that allows longitudinal analysis over time and is consistent with other procedures we have developed. Rats were trained to respond for ethanol in the presence of one stimulus (16 kHz tone; food Fixed Ratio (FR)150 and ethanol FR5), and for food in the under another stimulus (8 kHz tone; food and ethanol FR5). Then, recovery-like sessions with food predominant responding occurred in the presence of only the low-cost food stimulus. During these sessions, rats were exposed to non-reinforced graded stimuli alternation from 8 to 16 kHz alternating with the reinforced low-cost food stimulus. The number of responses on each (food and ethanol) lever before completing 5 responses on either lever was the main measure. Consistent with the earlier procedure, the current procedure showed that graded variation of tone from 8 to 16 kHz produced a graded increase in responding for ethanol compared to responding for food. In addition, longer periods of engaging in recovery-like responding shift the generalization function downwards. This procedure confirms the earlier pattern of stimulus generalization over longer periods of behavior consistent with recovery. This strengthens our hypothesis that shifts in attention to alcohol-related stimuli are important to the development of relapse resistance during recovery.
在此之前,我们开发了一种程序,该程序表明,如果替代行为的强化时间较长,那么之前导致饮酒的一系列刺激所引起的复发风险就会降低。复吸风险的降低可能是由于在反复参与替代行为的过程中,对刺激的注意力有所下降。然而,以前的这一程序耗时较长,与我们观察复饮风险变化的程序并不一致。本研究旨在复制之前的替代行为持续时间与饮酒刺激泛化转变之间的关系,使用的程序允许随着时间的推移进行纵向分析,并且与我们开发的其他程序一致。训练大鼠在一种刺激(16kHz 音调;食物固定比率(FR)150 和乙醇 FR5)下对乙醇做出反应,在另一种刺激(8kHz 音调;食物和乙醇 FR5)下对食物做出反应。然后,在仅有低成本食物刺激的情况下,大鼠会做出以食物为主的恢复性反应。在这些环节中,大鼠暴露于从 8 到 16 千赫兹的非强化分级刺激中,与强化的低成本食物刺激交替出现。主要测量大鼠在每个(食物和乙醇)杠杆上完成 5 次反应之前在任一杠杆上的反应次数。与之前的程序一致,目前的程序显示,与对食物的反应相比,从 8 到 16kHz 的音调分级变化会分级增加对乙醇的反应。此外,较长时间的恢复反应会使泛化功能向下移动。这一过程证实了之前的模式,即刺激泛化在较长时间的行为中与恢复一致。这加强了我们的假设,即对酒精相关刺激的注意力转移对恢复期抗复吸能力的发展非常重要。
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引用次数: 0
Impact of social vulnerability index on patients with alcohol-related liver disease 社会弱势指数对酒精相关肝病患者的影响。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-30 DOI: 10.1016/j.alcohol.2024.08.005

Introduction

Alcohol related liver disease (ALD) affects diverse communities with individual and social characteristics that can impact outcomes. The social vulnerability index (SVI) assigns a score between 0 and 1, where higher scores represent an increased risk of social vulnerability. We sought to assess the impact of SVI on outcomes of patients hospitalized with ALD with access to social support services.

Methods and materials

Hospitalizations for ALD at our institution between March and August 2019 were reviewed. All patients were assigned an SVI score based on their residential census tract. Per our standard practice, patients were screened by care coordinators to identify needs for rehabilitation counseling, and care coordination after discharge. Demographics, hepatic decompensation, critical care needs, readmission, and mortality were compared.

Results

Among 73 patients admitted for alcoholic hepatitis, 32 had a low SVI and 42 had a high SVI. African American patients were more likely to have a higher SVI (35% vs 0%, p=<0.001). No significant difference in outcomes based on SVI was noted.
There were 393 patients admitted for alcoholic cirrhosis including 166 with a low SVI and 227 with a high SVI. Patients that were African American (23.6% vs 5.5%, p=<0.001) or disabled (41.4% vs 29.5%, p = 0.008) had a higher SVI. No significant difference in outcomes based on SVI was noted.

Conclusion

Most patients admitted for ALD had a high SVI; however, SVI did not impact hospitalization outcomes.
导言:酒精相关肝病(ALD)影响着不同的社区,其个人和社会特征都会对治疗效果产生影响。社会脆弱性指数(SVI)在 0 到 1 之间打分,分数越高,社会脆弱性风险越大。我们试图评估 SVI 对获得社会支持服务的 ALD 住院患者预后的影响:我们对本机构 2019 年 3 月至 8 月期间因 ALD 住院的患者进行了回顾。所有患者均根据其居住人口普查区进行了 SVI 评分。根据我们的标准做法,护理协调员对患者进行筛查,以确定出院后的康复咨询和护理协调需求。对患者的人口统计学、肝功能失代偿、重症监护需求、再入院情况和死亡率进行了比较:在因酒精性肝炎入院的 73 名患者中,32 人的 SVI 值较低,42 人的 SVI 值较高。非裔美国患者更有可能具有较高的 SVI(35% vs 0%,p=结论:大多数因酒精性肝病入院的患者 SVI 值较高,但 SVI 值并不影响住院治疗效果。
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引用次数: 0
A novel alcohol+nicotine co-use self-administration procedure reveals sex differences and differential alteration of mesocorticolimbic TLR- and cholinergic-related neuroimmune gene expression in rats 一种新型的酒精+尼古丁共用自我给药程序揭示了大鼠的性别差异以及间皮质边缘TLR和胆碱能相关神经免疫基因表达的不同改变。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-27 DOI: 10.1016/j.alcohol.2024.08.003

Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex – prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and β2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence.

虽然酒精和尼古丁是两种最常见的共同使用药物,在美国,90%以上患有酒精使用障碍(AUD)的成年人同时也吸烟,但我们并不倾向于以这种方式研究酒精和尼古丁的使用。目前的研究试图在成年雄性和雌性 Long-Evans 大鼠中开发和评估一种新型的酒精和尼古丁共同获取自我给药模型(SA)。此外,这两种药物都与神经免疫功能有关,尽管它们的作用方式基本相反。长期饮酒会通过类收费受体(TLRs)增加神经炎症,进而增加酒精摄入量。相比之下,尼古丁则部分通过单体α7受体(ChRNa7)产生抗炎作用。在长期共同摄入(6 个月)后,大鼠在每天的训练中都能可靠地服用这两种药物,但雄性大鼠通常对酒精的反应更多,而雌性大鼠则对尼古丁的反应更多。这反映在血浆分析中,酒精和尼古丁的摄入量都与转化相关,因此在研究共同使用对行为和中枢神经系统功能的影响方面非常有价值。此外,雄性大鼠对酒精浓度的变化表现出敏感性,而雌性大鼠则对尼古丁浓度的变化表现出敏感性。接受过这种训练的大鼠也会产生焦虑表型。最后,我们评估了内侧前额叶皮层-边缘前区(mPFC-PL)、伏隔核核心(AcbC)和腹侧被盖区(VTA)中神经免疫相关基因表达的变化。在AcbC,α7的表达增加,β2的表达减少,尽管TLR基因表达增加,但促炎活动的标记物却减少了,这表明与尼古丁共同使用会从受体水平下游调节炎症状态。相比之下,在 mPFC-PL 中,α7 没有增加,但 TLR 和下游促炎标记物都增加了。综上所述,这些研究结果表明,在同时使用酒精和尼古丁的情况下,大脑存在区域和性别差异,并表明以尼古丁α7为靶点可能是治疗酒精和尼古丁共同依赖的一种新策略。
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引用次数: 0
The effects of moderate prenatal alcohol exposure on performance in hippocampal-sensitive spatial memory and anxiety tasks by adult male and female rat offspring 中度产前酒精暴露对成年雄性和雌性大鼠后代海马敏感空间记忆和焦虑任务表现的影响
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-08 DOI: 10.1016/j.alcohol.2024.08.002

Moderate prenatal alcohol exposure (mPAE) results in structural alterations to the hippocampus. Previous studies have reported impairments in hippocampal-sensitive tasks, but have not compared performance between male and female animals. In the present study, performance in hippocampal-sensitive spatial memory and anxiety behavior tests were compared across adult male and female saccharin (SACC) control mPAE Long-Evans rat offspring. Two tests of spatial memory were conducted that were aimed at assessing memory for recently acquired spatial information: A delayed spatial alternation task using an M-shaped maze and a delayed match-to-place task in the Morris water task. In both tasks, rats in SACC and mPAE groups showed similar learning and retention of a spatial location even after a 2-h interval between encoding and retention. A separate group of adult male and female SACC and mPAE rat offspring were tested for anxiety-like behaviors in the elevated plus-maze paradigm. In this test, both male and female mPAE rats exhibited a significantly greater amount of time and a greater number of head dips in the open arms, while locomotion and open arm entries did not differ between groups. The results suggest that mPAE produces a reduction in anxiety-like behaviors in both male and female rats in the elevated plus-maze.

中度产前酒精暴露(mPAE)会导致海马结构改变。以前的研究报告了海马敏感任务的损伤,但没有比较雌雄动物的表现。本研究比较了成年雄性和雌性糖精(SACC)对照 mPAE Long-Evans 大鼠后代在海马敏感空间记忆和焦虑行为测试中的表现。进行了两项空间记忆测试,旨在评估对最近获得的空间信息的记忆:一项是使用 M 型迷宫的延迟空间交替任务,另一项是莫里斯水任务中的延迟匹配到位置任务。在这两项任务中,SACC 组和 mPAE 组大鼠对空间位置的学习和保持情况相似,即使编码和保持之间间隔了 2 小时。另外一组成年雄性 SACC 和雌性 mPAE 大鼠后代在高架加迷宫范例中进行了焦虑行为测试。在该测试中,雄性和雌性 mPAE 大鼠在开放臂中表现出的时间和头下垂的次数都显著增加,而运动和进入开放臂的次数在组间没有差异。结果表明,mPAE 可减少雄性和雌性大鼠在高架加迷宫中的焦虑样行为。
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引用次数: 0
Alcohol-induced fibroblast growth factor 21 secretion is increased in individuals with alcohol use disorder 酒精诱导的成纤维细胞生长因子 21 在酒精使用障碍患者中分泌增加。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-05 DOI: 10.1016/j.alcohol.2024.08.001

Background

Alcohol use disorder (AUD) affects 5% of the global population. Despite its high prevalence, the pathophysiology of AUD remains enigmatic, hindering the development of novel therapeutics. Interestingly, the liver hormone fibroblast growth factor 21 (FGF21), which is currently in late-stage clinical trials for the treatment of non-alcoholic steatohepatitis, has been implicated by recent genome-wide association studies as a regulator of alcohol consumption.

Methods

This study aimed to evaluate plasma responses of FGF21 to an alcohol challenge in three groups: 15 males with AUD, 15 healthy males with a father with AUD (Predisposed), and 15 healthy males without any predisposition to AUD (Controls). All participants were investigated after an overnight fast. Assessments, including blood sampling and visual analog scale-assessed desire for alcohol intake, were performed before and for 10 h after ingesting 0.5 g alcohol per kg body weight over 10 min.

Results

The three groups were age and body-mass index-matched and had normal plasma concentrations of transaminases and FibroScan®-assessed elastography. Baseline FGF21 concentrations did not differ between groups, but individuals with AUD exhibited greater FGF21 responses to alcohol (area under the curve (AUC0–600 min): 954 ± 665 ng/ml × min (mean (standard deviation)) compared to Controls (AUC0–600 min: 453 ± 333 ng/ml × min, P = 0.03) but not Predisposed (AUC0–600 min: 556 ± 429 ng/ml × min, P = 0.11).

Conclusion

In conclusion, we demonstrate greater alcohol-induced FGF21 responses in individuals with AUD compared to healthy individuals without paternal predisposition to AUD, suggesting a role for FGF21 in AUD pathophysiology.

背景:酒精使用障碍(AUD)影响着全球 5% 的人口。尽管发病率很高,但 AUD 的病理生理学仍是一个谜,阻碍了新型疗法的开发。有趣的是,肝脏激素成纤维细胞生长因子 21 (FGF21)目前正处于治疗非酒精性脂肪性肝炎的后期临床试验阶段,最近的全基因组关联研究表明它是酒精消费的调节因子:本研究旨在评估三组人血浆中 FGF21 对酒精挑战的反应:15 名患有 AUD 的男性、15 名父亲患有 AUD 的健康男性(易患者)和 15 名没有任何 AUD 易患者的健康男性(对照组)。所有参与者均在一夜禁食后接受调查。在每公斤体重 10 分钟内摄入 0.5 克酒精之前和之后的 10 小时内进行评估,包括血液采样和视觉模拟量表评估酒精摄入欲望:结果:三组患者的年龄和体重指数相匹配,血浆中转氨酶浓度和纤维扫描弹性成像均正常。各组之间的 FGF21 基线浓度没有差异,但患有 AUD 的个体对酒精的 FGF21 反应更大(曲线下面积 (AUC0-600 min):954 ± 665 纳克/分钟):与对照组(AUC0-600 min:453 ± 333 ng/ml × min,P = 0.03)相比,AUD 患者对酒精的 FGF21 反应更大(曲线下面积 (AUC0-600 min):954 ± 665 ng/ml × min(平均值(标准偏差)),而易感人群(AUC0-600 min:556 ± 429 ng/ml × min,P = 0.11):总之,我们发现,与没有AUD父系易感性的健康人相比,AUD患者的酒精诱导FGF21反应更大,这表明FGF21在AUD病理生理学中发挥作用。
{"title":"Alcohol-induced fibroblast growth factor 21 secretion is increased in individuals with alcohol use disorder","authors":"","doi":"10.1016/j.alcohol.2024.08.001","DOIUrl":"10.1016/j.alcohol.2024.08.001","url":null,"abstract":"<div><h3>Background</h3><p>Alcohol use disorder (AUD) affects 5% of the global population. Despite its high prevalence, the pathophysiology of AUD remains enigmatic, hindering the development of novel therapeutics. Interestingly, the liver hormone fibroblast growth factor 21 (FGF21), which is currently in late-stage clinical trials for the treatment of non-alcoholic steatohepatitis, has been implicated by recent genome-wide association studies as a regulator of alcohol consumption.</p></div><div><h3>Methods</h3><p>This study aimed to evaluate plasma responses of FGF21 to an alcohol challenge in three groups: 15 males with AUD, 15 healthy males with a father with AUD (Predisposed), and 15 healthy males without any predisposition to AUD (Controls). All participants were investigated after an overnight fast. Assessments, including blood sampling and visual analog scale-assessed desire for alcohol intake, were performed before and for 10 h after ingesting 0.5 g alcohol per kg body weight over 10 min.</p></div><div><h3>Results</h3><p>The three groups were age and body-mass index-matched and had normal plasma concentrations of transaminases and FibroScan®-assessed elastography. Baseline FGF21 concentrations did not differ between groups, but individuals with AUD exhibited greater FGF21 responses to alcohol (area under the curve (AUC<sub>0–600 min</sub>): 954 ± 665 ng/ml × min (mean (standard deviation)) compared to Controls (AUC<sub>0–600 min</sub>: 453 ± 333 ng/ml × min, <em>P</em> = 0.03) but not Predisposed (AUC<sub>0–600 min</sub>: 556 ± 429 ng/ml × min, <em>P</em> = 0.11).</p></div><div><h3>Conclusion</h3><p>In conclusion, we demonstrate greater alcohol-induced FGF21 responses in individuals with AUD compared to healthy individuals without paternal predisposition to AUD, suggesting a role for FGF21 in AUD pathophysiology.</p></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0741832924001125/pdfft?md5=4c41d86367cd092ec5e9a21468750d4b&pid=1-s2.0-S0741832924001125-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141903903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Alcohol hangover versus dehydration revisited: The effect of drinking water to prevent or alleviate the alcohol hangover 重新审视宿醉与脱水:喝水对预防或缓解宿醉的影响。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-26 DOI: 10.1016/j.alcohol.2024.07.006

The alcohol hangover is a combination of negative mental and physical symptoms which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration (BAC) approaches zero. A popular theory suggests that dehydration is the primary cause of alcohol hangover and that the consumption of water could alleviate hangover symptoms. Here, the current evidence on the relationship between hangover severity, thirst, and water consumption is summarized. The positive correlations of the amount of water consumed with both hangover severity and thirst suggest that both dehydration and the hangover are co-occurring after-effects of alcohol consumption. While hangovers were typically relatively enduring, dehydration effects were usually mild and short-lasting. Survey data revealed that water consumption during or directly after alcohol consumption had only a modest effect in preventing next-day hangover. Also, the amount of water consumed during hangover was not related to changes of hangover severity and thirst. Thus, water consumption was not effective to alleviate the alcohol hangover. Taken together, these data suggests that alcohol hangover and dehydration are two co-occurring but independent consequences of alcohol consumption.

酒精宿醉是指一次饮酒后,当血液中酒精浓度(BAC)接近零时开始出现的一系列心理和生理上的不良症状。一种流行的理论认为,脱水是酒精宿醉的主要原因,而喝水可以缓解宿醉症状。在此,我们总结了宿醉严重程度、口渴和饮水量之间关系的现有证据。饮水量与宿醉严重程度和口渴程度呈正相关,这表明脱水和宿醉是饮酒后同时出现的后遗症。宿醉通常比较持久,而脱水效应通常比较轻微且持续时间较短。调查数据显示,在饮酒期间或饮酒后直接喝水对预防第二天宿醉的影响不大。此外,宿醉期间的饮水量与宿醉严重程度和口渴程度的变化无关。因此,喝水并不能有效缓解酒精宿醉。综上所述,这些数据表明,宿醉和脱水是饮酒后同时出现但又相互独立的两种后果。
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引用次数: 0
Sex and sobriety: Human brain structure and function in AUD abstinence 性与清醒:戒断澳大拉德的人脑结构和功能。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-26 DOI: 10.1016/j.alcohol.2024.07.003

Women are drinking alcohol as much as men for the first time in history. Women experience more health-related consequences from alcohol use disorder (AUD), like increased prevalence of alcohol-related cancers, faster progression of alcohol-related liver disease, and greater risk for relapse compared to men. Thus, sex differences in chronic alcohol use pose a substantial public health problem. Despite these evident sex differences, our understanding of how these differences present during alcohol abstinence is limited. Investigations of brain structure and function are therefore critical for disentangling factors that lead to sex differences in AUD abstinence. This review will discuss current human neuroimaging data on sex differences in alcohol abstinence, focusing on structural and functional brain measures. Current structural imaging literature reveals that abstinent men have smaller gray and white matter volume and weaker structural connectivity compared to control men. Interestingly, abstinent women do not show differences in brain structure when compared to controls; instead, abstinent women show a relation between alcohol use and decreased measures of brain structure. Current functional brain studies reveal that abstinent men exhibit greater brain activation and stronger task-based functional connectivity to aversive stimuli than control men, while abstinent women exhibit lesser brain activation and weaker task-based functional connectivity than control women. Together, the current literature suggests that sex differences persist well into alcohol abstinence and impact brain structure and function differently. Understanding how men and women differ during alcohol abstinence can improve our understanding of sex-specific effects of alcohol, which will be critical to augment treatment methods to better serve women.

有史以来,女性饮酒量首次与男性持平。与男性相比,女性因酒精使用障碍(AUD)而遭受更多与健康相关的后果,如与酒精相关的癌症发病率增加、与酒精相关的肝病进展更快、复发风险更高。因此,长期饮酒的性别差异是一个重大的公共卫生问题。尽管存在这些明显的性别差异,但我们对这些差异在戒酒期间是如何表现出来的了解还很有限。因此,对大脑结构和功能的研究对于揭示导致戒酒过程中性别差异的因素至关重要。本综述将讨论当前有关戒酒性别差异的人类神经成像数据,重点关注大脑结构和功能测量。目前的结构成像文献显示,与对照组男性相比,戒酒男性的灰质和白质体积较小,结构连接性较弱。有趣的是,与对照组相比,禁欲女性的大脑结构并没有显示出差异;相反,禁欲女性显示出酗酒与大脑结构测量下降之间的关系。目前的大脑功能研究显示,与对照组男性相比,禁欲男性的大脑激活程度更高,对厌恶刺激的任务功能连接性更强;而与对照组女性相比,禁欲女性的大脑激活程度较低,任务功能连接性较弱。总之,目前的文献表明,性别差异在戒酒后仍然存在,并对大脑结构和功能产生不同的影响。了解男性和女性在戒酒期间的差异可以提高我们对酒精的性别特异性影响的认识,这对改进治疗方法以更好地服务于女性至关重要。
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引用次数: 0
Emerging pharmacological targets for alcohol use disorder 治疗酒精使用障碍的新药理目标。
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-26 DOI: 10.1016/j.alcohol.2024.07.007

Alcohol Use Disorder (AUD) remains a challenging condition with limited effective treatment options; however new technology in drug delivery and advancements in pharmacology have paved the way for discovery of novel therapeutic targets. This review explores emerging pharmacological targets that offer new options for the management of AUD, focusing on the potential of somatostatin (SST), vasoactive intestinal peptide (VIP), glucagon-like peptide-1 (GLP-1), nociceptin (NOP), and neuropeptide S (NPS). These targets have been selected based on recent advancements in preclinical and clinical research, which suggest their significant roles in modulating alcohol consumption and related behaviors. SST dampens cortical circuits, and targeting both the SST neurons and the SST peptide itself presents promise for treating AUD and various related comorbidities. VIP neurons are modulated by alcohol and targeting the VIP system presents an unexplored avenue for addressing alcohol exposure at various stages of development. GLP-1 interacts with the dopaminergic reward system and reduces alcohol intake. Nociceptin modulates mesolimbic circuitry and agonism and antagonism of nociceptin receptor offers a complex but promising approach to reducing alcohol consumption. NPS stands out for its anxiolytic-like effects, particularly relevant for the anxiety associated with AUD. This review aims to synthesize the current understanding of these targets, highlighting their potential in developing more effective and personalized AUD therapies, and underscores the importance of continued research in identifying and validating novel targets for treatment of AUD and comorbid conditions.

酒精使用障碍(AUD)仍然是一种具有挑战性的疾病,有效的治疗方案有限;然而,新的给药技术和药理学的进步为发现新的治疗靶点铺平了道路。本综述探讨了为治疗 AUD 提供新选择的新兴药理学靶点,重点关注体生长抑素 (SST)、血管活性肠肽 (VIP)、胰高血糖素样肽-1 (GLP-1)、神经肽 (NOP) 和神经肽 S (NPS) 的潜力。选择这些靶点的依据是临床前和临床研究的最新进展,这些进展表明它们在调节酒精消费和相关行为方面发挥着重要作用。SST 可抑制大脑皮层回路,以 SST 神经元和 SST 肽本身为靶点有望治疗 AUD 和各种相关合并症。VIP神经元受酒精调节,针对VIP系统的研究为解决不同发育阶段的酒精暴露问题提供了一条尚未探索的途径。GLP-1 与多巴胺能奖赏系统相互作用,减少酒精摄入。痛觉素能调节间叶回路,痛觉素受体的激动和拮抗作用为减少酒精摄入提供了一种复杂但有前景的方法。NPS 具有类似抗焦虑的作用,尤其适用于与 AUD 相关的焦虑症。本综述旨在综述目前对这些靶点的认识,强调它们在开发更有效和个性化的 AUD 治疗方法方面的潜力,并强调继续开展研究以确定和验证治疗 AUD 和合并症的新靶点的重要性。
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引用次数: 0
Sex Differences in Mouse Models of Voluntary Alcohol Drinking and Abstinence-Induced Negative Emotion 小鼠自愿饮酒和禁酒诱发负性情绪模型的性别差异
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-23 DOI: 10.1016/j.alcohol.2024.07.004

Alcohol Use Disorder (AUD) is a growing problem worldwide, causing an incredible burden on health and the economy. Though AUD impacts people of all backgrounds and demographics, increasing evidence has suggested robust sex differences in alcohol drinking patterns and AUD-induced negative emotionality or hyperkatifeia. Rates of problematic drinking have significantly risen among women, and women face more severe negative emotional consequences in abstinence such as increased risk of comorbidity with an anxiety or mood disorder and more severe symptoms of depression. As such, a bevy of preclinical literature using contingent methods of alcohol (ethanol) consumption has amassed in recent years to better understand sex as a biological variable in alcohol drinking and abstinence-induced negative emotionality. Mice are widely used to model alcohol drinking, as they are conducive to genetic manipulation strategies, and many strains will voluntarily consume alcohol. Sex-specific results from these mouse studies, however, have been inconsistent. Therefore, this review aims to summarize the current knowledge on sex differences in AUD-related contingent ethanol drinking and abstinence-induced negative emotionality in mice. Various contingent mouse drinking models and negative emotional-based behavioral paradigms are introduced and subsequently discussed in the context of sex differences to show increasing indications of sex specificity in mouse preclinical studies of AUD. With this review, we hope to inform future research on potential sex differences in preclinical mouse models of AUD and provide mounting evidence supporting the need for more widespread inclusion of preclinical female subjects in future studies.

酒精使用障碍(AUD)是一个日益严重的世界性问题,给健康和经济造成了巨大负担。尽管 AUD 影响着各种背景和人口结构的人群,但越来越多的证据表明,在饮酒模式和 AUD 引起的负面情绪或过度情绪方面存在着明显的性别差异。女性的问题性饮酒率明显上升,女性在戒酒时面临更严重的负面情绪后果,如合并焦虑或情绪障碍的风险增加,抑郁症状更严重。因此,为了更好地了解性别作为饮酒和戒酒诱发负面情绪的一个生物变量,近年来积累了大量使用酒精(乙醇)消费或然法的临床前文献。小鼠被广泛用于建立饮酒模型,因为它们有利于遗传操作策略,而且许多品系的小鼠会自愿饮酒。然而,这些小鼠研究的性别特异性结果并不一致。因此,本综述旨在总结小鼠与 AUD 相关的或然乙醇饮酒和禁欲诱导的负性情绪的性别差异的现有知识。本综述介绍了各种或然性小鼠饮酒模型和基于负性情绪的行为范式,随后在性别差异的背景下进行了讨论,以显示在 AUD 的小鼠临床前研究中越来越多的性别特异性迹象。通过这篇综述,我们希望为今后有关 AUD 临床前小鼠模型中潜在性别差异的研究提供信息,并提供越来越多的证据支持在今后的研究中更广泛地纳入临床前女性受试者的必要性。
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引用次数: 0
Interneuron-selective HCN channel knockdown in prelimbic cortex of female rats mimics effects of chronic ethanol exposure 敲除雌性大鼠前边缘皮层的神经元选择性 HCN 通道可模拟慢性乙醇暴露的影响
IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Pub Date : 2024-07-19 DOI: 10.1016/j.alcohol.2024.07.005

Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague–Dawley rats, indicative of a fundamental sex difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol induces facilitated working memory performance via down-regulation of these channels’ activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.

我们的实验室以前曾发现,慢性乙醇暴露会增强雌性成年 Sprague-Dawley 大鼠的工作记忆能力,而雄性大鼠则不会,这表明大脑皮层的可塑性存在根本性的性别差异。最近的研究进一步发现,雌性大鼠在长期接触乙醇后,抑制性马丁诺蒂中间神经元中 HCN 介导的通道活性明显降低,而雄性大鼠则没有类似现象。根据这些观察结果,我们推测酒精会通过下调这些通道在中间神经元中的活性来促进工作记忆的表现。为了验证这一假设,我们采用了一种与 Pol-II 兼容的 shRNA 表达系统,有针对性地敲除这些细胞中的 HCN 通道活性,并在延迟非匹配抽样(NMS)T-迷宫测试中测量其表现,以评估其对工作记忆表现的影响。在敲除HCN通道后,工作记忆的基线表现明显增强,这表明神经元间表达的HCN在认知要求较高的任务中对维持最佳皮层网络活动起着关键作用。与之前的观察结果一致,乙醇暴露会导致 NMS T 迷宫表现增强,但在施用酒精后,scram 和 hcn-shRNA 感染组都观察到了工作记忆表现的提升。因此,我们得出结论,尽管神经元间表达的 HCN 通道在大脑皮层 HCN 总表达量中仅占一小部分,但它们对维持工作记忆过程做出了重大贡献。不过,下调的 HCN 通道活性似乎并不足以单独表现出酒精诱导的雌性大鼠在急性戒断期工作记忆能力的增强。
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