Addiction neuroscience最新文献_第6页

Proportion and distribution of neurotransmitter-defined cell types in the ventral tegmental area and substantia nigra pars compacta 腹侧被盖区和黑质紧密团中神经递质定义细胞类型的比例和分布

Addiction neuroscience

Pub Date : 2024-10-28 DOI: 10.1016/j.addicn.2024.100183

William S. Conrad , Lucie Oriol , Grace J. Kollman , Lauren Faget , Thomas S. Hnasko

Most studies on the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) have focused on dopamine neurons and their role in processes such as motivation, learning, movement, and associated disorders such as addiction and Parkinson's disease. However there has been increasing attention on other VTA and SNc cell types that release GABA, glutamate, or a combination of neurotransmitters. Yet the relative distributions and proportions of neurotransmitter-defined cell types across VTA and SNc has remained unclear. Here, we used fluorescent in situ hybridization in male and female mice to label VTA and SNc neurons that expressed mRNA encoding the canonical vesicular transporters for dopamine, GABA, or glutamate: vesicular monoamine transporter (VMAT2), vesicular GABA transporter (VGAT), and vesicular glutamate transporter (VGLUT2). Within VTA, we found that no one type was particularly more abundant, instead we observed similar numbers of VMAT2+ (44 %), VGAT+ (37 %) and VGLUT2+ (41 %) neurons. In SNc we found that a slight majority of neurons expressed VMAT2 (54 %), fewer were VGAT+ (42 %), and VGLUT2+ neurons were least abundant (16 %). Moreover, 20 % of VTA neurons and 10 % of SNc neurons expressed more than one vesicular transporter, including 45 % of VGLUT2+ neurons. We also assessed within VTA and SNc subregions and found remarkable heterogeneity in cell-type composition. And by quantifying density across both anterior-posterior and medial-lateral axes we generated heatmaps to visualize the distribution of each cell type. Our data complement recent single-cell RNAseq studies and support a more diverse landscape of neurotransmitter-defined cell types in VTA and SNc than is typically appreciated.

有关腹侧被盖区（VTA）和黑质紧密团结区（SNc）的大多数研究都集中在多巴胺神经元及其在动机、学习、运动等过程中的作用，以及成瘾和帕金森病等相关疾病中的作用。然而，人们越来越关注其他释放 GABA、谷氨酸或多种神经递质的 VTA 和 SNc 细胞类型。然而，神经递质定义的细胞类型在 VTA 和 SNc 中的相对分布和比例仍不清楚。在这里，我们在雄性和雌性小鼠体内使用荧光原位杂交技术标记了表达编码多巴胺、GABA 或谷氨酸典型囊泡转运体 mRNA 的 VTA 和 SNc 神经元：囊泡单胺转运体 (VMAT2)、囊泡 GABA 转运体 (VGAT) 和囊泡谷氨酸转运体 (VGLUT2)。在 VTA 中，我们发现没有哪种类型的神经元特别多，相反，我们观察到的 VMAT2+ 神经元（44%）、VGAT+ 神经元（37%）和 VGLUT2+ 神经元（41%）的数量相似。我们发现，SNc 中表达 VMAT2 的神经元略占多数（54%），VGAT+ 神经元较少（42%），VGLUT2+ 神经元最少（16%）。此外，20% 的 VTA 神经元和 10% 的 SNc 神经元表达一种以上的囊泡转运体，其中包括 45% 的 VGLUT2+ 神经元。我们还对 VTA 和 SNc 亚区域进行了评估，发现细胞类型组成存在显著的异质性。通过对前后轴和内外侧轴的密度进行量化，我们生成了热图，以直观显示每种细胞类型的分布情况。我们的数据补充了最近的单细胞 RNAseq 研究，并支持在 VTA 和 SNc 中神经递质定义的细胞类型比通常所理解的更加多样化。

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引用次数: 0

Subregion specific monoaminergic signaling in the female rat striatum during nicotine abstinence 尼古丁戒断期间雌性大鼠纹状体中特定亚区的单胺能信号传导

Addiction neuroscience

Pub Date : 2024-10-24 DOI: 10.1016/j.addicn.2024.100184

Erika Lucente, Davide Cadeddu, Christian E Edvardsson, Mia Ericson, Elisabet Jerlhag, Louise Adermark

Women report more negative effect during nicotine abstinence, a state that may increase the risk of relapse. As monoamines play a key role in mood regulation the aim of this study was to outline changes in monoaminergic signaling during nicotine abstinence. To this end, tissue levels of dopamine and serotonin, as well as the impact displayed by the dopamine D2 receptor agonist quinpirole or 5-HT on excitatory neurotransmission was assessed in female rats subjected to three weeks of nicotine exposure followed by abstinence. Studies were conducted in the nucleus accumbens (nAc), a structure associated with the acute rewarding properties of nicotine, and the dorsolateral striatum (DLS), a region linked to the formation of habits. Data demonstrate that the monoaminergic profile is subregions specific, with higher levels of dopamine in the DLS, but higher levels of serotonin in the nAc. The influence displayed by quinpirole or 5-HT on excitatory neurotransmission was, however, subregion-independent. Repeated exposure to nicotine produced a robust and long-lasting behavioral sensitization to the locomotor stimulatory properties of nicotine, with no sustained changes in monoaminergic profiles when assessed in striatal tissue after five days of abstinence. However, ex vivo electrophysiological recordings demonstrated a subregion specific change in the responsiveness to bath perfused 5-HT, with a blunted response in the DLS, and enhanced synaptic depression in the nAc. In conclusion, while nicotine abstinence was not associated with sustained changes in tissue monoamine levels, repeated nicotine exposure produced subregion-specific neuroplasticity which might contribute to the high risk of nicotine relapse.

女性在尼古丁戒断期间会产生更多的负面影响，这种状态可能会增加复吸的风险。由于单胺类物质在情绪调节中起着关键作用，本研究旨在概述尼古丁戒断期间单胺类物质信号传导的变化。为此，研究人员评估了雌性大鼠多巴胺和血清素的组织水平，以及多巴胺 D2 受体激动剂喹吡罗或 5-HT 对兴奋性神经递质的影响。研究在与尼古丁急性奖赏特性相关的凹凸核（nAc）和与习惯形成相关的背外侧纹状体（DLS）进行。数据显示，单胺类物质的分布具有亚区域特异性，在 DLS 中多巴胺水平较高，而在 nAc 中血清素水平较高。然而，喹吡酮或5-羟色胺对兴奋性神经递质的影响与亚区域无关。重复暴露于尼古丁会对尼古丁的运动刺激特性产生强烈而持久的行为敏感性，而在戒断尼古丁五天后对纹状体组织进行评估时，单胺类神经递质没有发生持续变化。然而，体外电生理记录显示，对浴灌5-羟色胺的反应有亚区域特异性变化，DLS的反应减弱，而nAc的突触抑制增强。总之，虽然尼古丁戒断与组织单胺水平的持续变化无关，但重复尼古丁暴露会产生亚区域特异性神经可塑性，这可能是尼古丁复吸风险高的原因之一。

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引用次数: 0

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice 口服芬太尼和戒断芬太尼会损害雌雄小鼠的恐惧消退学习并增强杏仁核基底外侧主神经元的兴奋-抑制平衡

Addiction neuroscience

Pub Date : 2024-10-15 DOI: 10.1016/j.addicn.2024.100182

Anthony M. Downs , Gracianne Kmiec , Zoé A. McElligott

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having increased withdrawal symptoms as compared to females, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

在过去几年中，阿片类药物过量致死的人数有所增加，主要原因是在不受管制的药物供应中，像芬太尼这样的强效合成阿片类药物的供应量有所增加。在过去几年中，药物供应的变化，尤其是含有芬太尼的假药的出现，使得口服阿片类药物成为一种更常见的给药途径。在这里，我们采用黑暗饮水（DiD）范式，利用雄性和雌性小鼠在5周内不断增加的芬太尼浓度来模拟口服芬太尼的自我给药。雌性和雄性小鼠的芬太尼消耗量在30微克/毫升剂量时达到峰值，其中雌性小鼠的芬太尼消耗量明显高于雄性小鼠。小鼠消耗了足够的芬太尼，因此使用纳洛酮后会出现戒断症状，尽管药理暴露量较低，但雄性小鼠的戒断症状比雌性小鼠严重。我们还进行了行为测定，以测量芬太尼戒断期间的回避行为和寻求奖赏的行为。雌性小鼠在开阔地实验中的回避行为减少，而雄性小鼠在光/暗箱实验中的回避行为增加。在蔗糖偏好试验中，雌性小鼠也表现出更高的奖励寻求行为。服用芬太尼的雌雄小鼠在恐惧条件反射后的诱导恐惧消退学习能力受损，兴奋性突触驱动力增加，BLA主神经元的兴奋性增加。我们的实验证明，长期口服芬太尼会导致广泛的生理和行为紊乱。该模型有助于进一步研究芬太尼戒断综合征以及与长期芬太尼戒断相关的行为和神经可塑性。

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引用次数: 0

Perirhinal cortex to the nucleus accumbens circuit in novelty salience following methamphetamine self-administration 甲基苯丙胺自我给药后新奇感显著性中的边缘皮层至脑核回路

Addiction neuroscience

Pub Date : 2024-10-14 DOI: 10.1016/j.addicn.2024.100181

Katharine H. Nelson , Dylan L. Freels , Jordan S. Carter , Samuel K. Wood , Adam R. Denton , Jordan L. Hopkins , Sarah T. Goldsmith , Stacia I. Lewandowski , Michael D. Scofield , Carmela M. Reichel

Methamphetamine (meth) use disorder is part of an overarching use disorder that encompasses continued drug seeking and an increased risk of returning to drug use following periods of abstaining. Chronic meth use results in drug-induced cortical plasticity in the perirhinal cortex (PRC) that mediates responses to novelty. PRH projection targets are numerous and include the nucleus accumbens core (NAc). Whereas the PRH-prefrontal cortex is involved in object recognition; we propose that the PRHNAc is involved in novelty salience. Rats underwent short-access (ShA, 1 hr) or long-access (LgA, 6 hr) meth self-administration (SA). We then used a dual viral strategy to inhibit or activate PRHNAc during a novel cue test in which rats were presented with meth‑associated and novel levers. Response patterns on these levers differ depending on the meth access protocol: ShA meth SA results in equal responding on both novel- and meth‑associated levers, whereas LgA meth results in perseverative responding on the meth‑associated lever. Inactivation of the PRHNAc increased responding on the meth lever relative to the novel lever, resulting in a LgA behavioral phenotype. In contrast, activation in LgA rats was without a behavioral effect. We also report that male LgA sucrose SA animals perseverated on the novel lever rather than the meth‑associated lever, which contrast their meth SA counter parts and female specific patterns of behavior. These data open a new line of interest in the role of the PRHNAc circuit in novelty salience through identification of the behavioral relevance of this circuit.

甲基苯丙胺（冰毒）吸食障碍是总体吸食障碍的一部分，包括持续寻求毒品和戒断后重新吸食毒品的风险增加。长期吸食冰毒会导致脐周皮质（PRC）在药物诱导下发生皮质可塑性变化，从而介导对新奇事物的反应。PRH的投射目标很多，包括伏隔核（NAc）。PRH-前额叶皮层参与物体识别，而我们认为PRHNAc参与新奇事物的显著性。我们对大鼠进行了短程（ShA，1小时）或长程（LgA，6小时）甲基自我给药（SA）。然后，我们使用双重病毒策略在新线索测试中抑制或激活 PRHNAc。大鼠对这些杠杆的反应模式因接触甲基苯丙胺的方案而异：ShA 冰毒 SA 会导致大鼠对新颖和与冰毒相关的杠杆做出相同的反应，而 LgA 冰毒则会导致大鼠对与冰毒相关的杠杆做出锲而不舍的反应。PRHNAc失活会增加在甲基杠杆上的反应，从而导致 LgA 行为表型。相反，激活 PRHNAc 对 LgA 大鼠的行为没有影响。我们还报告说，雄性 LgA 蔗糖 SA 动物坚持使用新杠杆，而不是甲基相关杠杆，这与它们的甲基 SA 动物和雌性特定行为模式形成了鲜明对比。这些数据通过鉴定 PRHNAc 电路的行为相关性，为研究该电路在新奇事物显著性中的作用开辟了一条新途径。

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引用次数: 0

Post-mortem human brain analysis of the ventral pallidum in alcohol use disorder 对酒精使用障碍患者腹侧苍白球的死后人脑分析

Addiction neuroscience

Pub Date : 2024-10-11 DOI: 10.1016/j.addicn.2024.100180

Ameer Elena Rasool , Cormac Peat , Jie Liu, Greg Sutherland, Asheeta A. Prasad

Objective

Alcohol use disorder (AUD) is characterised by cycles of alcohol misuse, abstinence, and relapse. The neurobiology of AUD strongly implicates the role of the ventral pallidum (VP) in a variety of drugs of abuse, including alcohol. Pre-clinical studies have demonstrated critical role of parvalbumin and calretinin neurons in the VP in modulating relapse, mood, and motivation. However, there are a limited studies examining the VP at the cellular level in AUD in humans.

Method

Post-mortem human brain tissue of AUD (n = 11), remission (n = 6), and control brains (n = 12) were processed for immunohistochemistry to examine the presence and changes in parvalbumin and calretinin neurons in the VP.

Results

Similar to pre-clinical rodent models, parvalbumin and calretinin neurons were present in the VP, although no significant difference was found in their number or morphology across all AUD, remission, and control brains.

Conclusion

The presence of parvalbumin and calretinin neurons in the VP was confirmed across all groups. This is particularly important as it supports the translatability of previous animal studies regarding the role of parvalbumin and calretinin neurons in AUD, and thus further implicates the VP in the neurobiology of AUD in humans. As there are no distinctions in the number or morphology of these neurons, their significance likely lies in their activity. The presence of both parvalbumin and calretinin in humans, particularly in both control and AUD cases supports translational capacity from preclinical findings is more feasible.

目标酒精使用障碍（AUD）的特征是酒精滥用、戒断和复发的循环。AUD 的神经生物学与腹侧苍白球（VP）在包括酒精在内的多种药物滥用中的作用密切相关。临床前研究已经证明，VP 中的parvalbumin 和 calretinin 神经元在调节复发、情绪和动机方面起着关键作用。方法对AUD（11例）、缓解期（6例）和对照组（12例）的死后人类脑组织进行免疫组化处理，以检测VP中副发光素和钙视蛋白神经元的存在和变化。结果与临床前啮齿类动物模型相似，VP 中存在副发光素和钙网蛋白神经元，但在所有 AUD、缓解组和对照组大脑中，其数量和形态均无显著差异。这一点尤为重要，因为它支持了之前关于副发光素和钙视蛋白神经元在 AUD 中作用的动物研究的可转化性，从而进一步将 VP 与人类 AUD 的神经生物学联系起来。由于这些神经元在数量和形态上没有区别，其重要性可能在于它们的活性。人类体内，尤其是在对照组和 AUD 病例中同时存在副视蛋白和钙视蛋白，这证明临床前研究结果的转化能力更加可行。

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引用次数: 0

Targeting the ventral pallidum in obesity 针对肥胖症的腹侧苍白球

Addiction neuroscience

Pub Date : 2024-10-11 DOI: 10.1016/j.addicn.2024.100179

Lisa Z. Fang , Yvan M. Vachez

Obesity remains a global health challenge with escalating prevalence and imperfect treatments, necessitating novel therapeutic interventions. Hedonic feeding has been identified as a main driver of weight gain, leading to obesity. Therefore, targeting the neural circuits that regulate hedonic intake to reverse or treat obesity may boast a promising strategy.

The ventral pallidum (VP), a crucial component of the brain's reward circuitry, plays a pivotal role in encoding reward value and reinforcing motivated behaviors, including food intake. This review highlights the work cementing the role of the VP in feeding regulation, and delves into the connectivity between the VP and other brain regions governing energy homeostasis and hedonic feeding behaviors. We also examine the evidence suggesting that dysregulation within the VP contributes to hyperphagia and the development of obesity. Lastly, we discuss the VP as a possible target for focused intervention. Deep brain stimulation for obesity has been under investigation for several years but current electrode targets yield mixed, dissatisfying results.

While considerable progress has been made in elucidating the VP's role in feeding and obesity, several challenges remain in translating these findings into clinical interventions. Dissecting the diverse neurochemical, neuroanatomical, and projection connectivity of the VP will allow us to harness the full therapeutic potential of VP-based interventions, and may open avenues for developing targeted therapies to address the multifaceted nature of obesity.

肥胖症仍然是一个全球性的健康挑战，其发病率不断上升，但治疗方法却不完善，因此有必要采取新的治疗干预措施。享乐性摄食已被确认为体重增加的主要驱动因素，从而导致肥胖。腹侧苍白球（VP）是大脑奖赏回路的重要组成部分，在编码奖赏价值和强化动机行为（包括食物摄入）方面发挥着关键作用。这篇综述重点介绍了巩固腹外侧皮层在摄食调节中作用的研究成果，并深入探讨了腹外侧皮层与其他管理能量平衡和享乐性摄食行为的脑区之间的联系。我们还研究了一些证据，这些证据表明，VP 内的调节失调会导致多食和肥胖的发生。最后，我们讨论了将 VP 作为重点干预目标的可能性。虽然在阐明VP在进食和肥胖中的作用方面取得了很大进展，但要将这些发现转化为临床干预措施仍面临一些挑战。剖析VP的神经化学、神经解剖和投射连接的多样性将使我们能够充分利用基于VP的干预措施的治疗潜力，并为开发靶向疗法以解决肥胖症的多面性开辟道路。

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引用次数: 0

Fentanyl demand and seeking in female rats: Role of the orexin system and estrous cycle 雌性大鼠对芬太尼的需求和寻求：奥曲肽系统和发情周期的作用

Addiction neuroscience

Pub Date : 2024-10-09 DOI: 10.1016/j.addicn.2024.100178

David De Sa Nogueira , Chuhyon Corwin , Yogesh Rakholia , Varnitha Punnuru , Meghana Nampally , Amy S. Kohtz , Gary Aston-Jones

The orexin system plays a major role in drug reward. Orexin-1 receptor (OxR1) blockade reduces fentanyl demand in males. However, there are a number of sex differences in the orexin system, and it is unclear how OxR1 antagonism would decrease fentanyl demand in females. Furthermore, the relationships between the estrous cycle and fentanyl intake are yet to be delineated.

Here, we conducted a behavioral economics (BE) procedure in female rats to assess the effects of the OxR1 antagonist SB-334867 on fentanyl demand before and after short-(ShA), long- (LgA) or intermittent-access (IntA) self-administration of fentanyl; we also tested the effect of SB-334867 on cued reinstatement of fentanyl seeking. Finally, we measured the impact of the estrous cycle on fentanyl demand, intake and seeking.

Results showed that in females SB-334867 did not consistently modulate demand for fentanyl before or after chronic access periods. However, SB-334867 at 30mg/kg reduced the number of active lever presses during cued-reinstatement of fentanyl seeking. We also found that fentanyl self-administration disrupted estrous cyclicity, in particular proestrus epochs, an effect that depended on short versus chronic access. Furthermore, extended access to fentanyl shifted the role of progesterone from facilitation of fentanyl demand during short periods, to attenuation of fentanyl demand after long term exposure. These results indicate that an orexin-based therapy in women for treating opioid use disorder must consider prior drug history as well as cycle phase.

奥曲肽系统在药物奖赏中扮演着重要角色。阻断奥曲肽-1 受体（OxR1）可减少男性对芬太尼的需求。然而，奥曲肽系统存在许多性别差异，目前还不清楚 OxR1 拮抗如何降低女性对芬太尼的需求。在这里，我们对雌性大鼠进行了行为经济学（BE）程序，以评估 OxR1 拮抗剂 SB-334867 在短时间（ShA）、长时间（LgA）或间歇性（IntA）自我给药芬太尼前后对芬太尼需求的影响；我们还测试了 SB-334867 对芬太尼寻求的诱导恢复的影响。最后，我们测量了发情周期对芬太尼需求量、摄入量和寻求量的影响。结果表明，在女性中，SB-334867 并未持续调节慢性获取期前后对芬太尼的需求量。然而，30 毫克/千克的 SB-334867 可减少在芬太尼诱导恢复过程中主动按下杠杆的次数。我们还发现，芬太尼自我给药会扰乱发情周期，尤其是发情前期，这种影响取决于短期和长期给药。此外，延长使用芬太尼的时间会使孕酮的作用从短时间内促进对芬太尼的需求转变为长期接触后减弱对芬太尼的需求。这些结果表明，基于奥曲肽的女性阿片类药物使用障碍治疗方法必须考虑之前的吸毒史和周期阶段。

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引用次数: 0

The effects of amphetamine exposure on stress susceptibility in mice 接触苯丙胺对小鼠应激易感性的影响

Addiction neuroscience

Pub Date : 2024-09-28 DOI: 10.1016/j.addicn.2024.100176

Anne K. Eby , Benjamin D. Sachs

Substance use disorders (SUDs) and their many psychiatric comorbidities, including major depression and anxiety disorders, are characterized by significant sex differences. Although the causes of SUDs and their psychiatric comorbidities remain unknown, stress has been heavily implicated in their etiology. Indeed, one leading hypothesis regarding the basis of clinically observed sex differences in psychopathology argues that differences in stress susceptibility and stress exposure play key roles. Consistent with this, differences in stress susceptibility and reactivity in females compared to males have been documented across multiple species. A wide range of environmental, genetic, and epigenetic factors are also thought to impact stress susceptibility, but whether there are sex differences in the effects of specific susceptibility factors remains understudied. Preclinical work suggests that a history of cocaine exposure can increase susceptibility to stress in males, but whether similar effects occur in females following stimulant exposure has not been established. The current work examined the impact of repeated amphetamine administration on subsequent susceptibility to mild sub-chronic stress in male and female mice. In addition to examining behavior, potential sex differences in the effects of stress and amphetamine on the expression of several genes were evaluated. Our results reveal several significant sex differences in the behavioral effects of amphetamine and stress in the elevated plus maze, forced swim test, and novelty-suppressed feeding test. However, in contrast to our initial hypothesis, a history of amphetamine did not lead to an overall increase in stress susceptibility across multiple tests in males or females.

物质使用障碍（SUDs）及其多种精神并发症，包括重度抑郁症和焦虑症，都有明显的性别差异。尽管导致药物滥用性障碍及其精神并发症的原因尚不清楚，但压力在很大程度上与这些疾病的病因有关。事实上，关于临床观察到的精神病理学性别差异的一个主要假说认为，压力易感性和压力暴露的差异起着关键作用。与此相一致的是，在多个物种中都记录了雌性与雄性在压力易感性和反应性方面的差异。各种环境、遗传和表观遗传因素也被认为会影响压力易感性，但特定易感性因素的影响是否存在性别差异仍未得到充分研究。临床前研究表明，可卡因接触史会增加男性对压力的易感性，但女性在接触兴奋剂后是否会产生类似的影响尚未确定。目前的研究考察了重复服用苯丙胺对雄性和雌性小鼠随后对轻度亚慢性应激的易感性的影响。除了研究行为之外，我们还评估了压力和苯丙胺对多个基因表达影响的潜在性别差异。我们的结果表明，在高架加迷宫、强迫游泳试验和新奇抑制摄食试验中，苯丙胺和应激对行为的影响存在几种明显的性别差异。然而，与我们最初的假设不同的是，在多项测试中，苯丙胺史并没有导致雄性或雌性对应激的敏感性全面提高。

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引用次数: 0

Impacts of endogenous opioid blockade and sex on working memory among ad-libitum and abstinent smokers and non-smokers 内源性阿片类药物阻断和性别对吸烟者和非吸烟者工作记忆的影响

Addiction neuroscience

Pub Date : 2024-09-26 DOI: 10.1016/j.addicn.2024.100177

Ryan Johnson , Briana N. DeAngelis , Motohiro Nakajima , Sharon S. Allen , Mustafa al'Absi

Background

Research examining the effects of opioid receptor antagonists on working memory is limited by small sample sizes that are often comprised of only male participants. Moreover, they have yielded mixed findings, and no studies have examined such effects in the context of chronic nicotine use and temporary nicotine withdrawal.

Methods

Male and female participants completed two lab visits at which they were administered either 50 mg naltrexone or an identical placebo (one at each lab using double-blind, counterbalanced administration). After a medication absorption period, performance on a mental arithmetic (working memory) task was assessed by number of correct responses, errors, and number of attempts. Participants were either non-smokers or regular smokers who were randomly assigned to use nicotine ad-libitum or to abstain from nicotine for 24 h prior to both lab visits.

Results

The results indicate a significant main effect of opioid blockade on number of correct answers and accuracy rate during the mental arithmetic task, with poorer performance after opioid blockade compared to placebo. In addition, compared to male participants, female participants made fewer answer attempts, had fewer correct answers, and a lower accuracy rate. We did not find evidence of any differences based on smoking group (non-smoker, smoking abstinence, or ad-libitum smoking), nor were there any significant interaction effects.

Conclusions

The findings suggest a modulating role of the endogenous opioid system in working memory function. Further investigation is needed to help identify the underlying mechanisms explaining the effects of the endogenous opioid system on working memory.

背景有关阿片受体拮抗剂对工作记忆影响的研究受到样本量小的限制，通常只有男性参与者。方法男性和女性参加者完成两次实验室访问，在访问过程中分别服用 50 毫克纳曲酮或相同的安慰剂（每个实验室一次，采用双盲、平衡给药）。药物吸收期结束后，根据正确反应次数、错误次数和尝试次数对心算（工作记忆）任务的表现进行评估。结果表明，阿片类药物阻断对心算任务中的正确答案数和正确率有显著的主效应，与安慰剂相比，阿片类药物阻断后的表现更差。此外，与男性参与者相比，女性参与者尝试回答的次数更少，正确答案更少，准确率也更低。我们没有发现基于吸烟组（不吸烟、戒烟或吸二手烟）的任何差异，也没有发现任何显著的交互效应。研究结果表明，内源性阿片系统对工作记忆功能有调节作用，需要进一步研究，以帮助确定内源性阿片系统对工作记忆影响的潜在机制。

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引用次数: 0

Opioid drug seeking after early-life adversity: a role for delta opioid receptors 早年逆境后的阿片类药物寻求：δ阿片受体的作用

Addiction neuroscience

Pub Date : 2024-09-19 DOI: 10.1016/j.addicn.2024.100175

Sophia C. Levis , Matthew T. Birnie , Yiyan Xie , Noriko Kamei , Puja V. Kulkarni , Johanna S. Montesinos , Christina R. Perrone , Catherine M. Cahill , Tallie Z. Baram , Stephen V. Mahler

Opioid use disorder (OUD) is associated with a history of early-life adversity (ELA), an association that is particularly strong in women. In a rodent model, we previously found that ELA enhances risk for opioid addiction selectively in females, but the mechanisms for this effect are unclear. Here, we show that ELA robustly alters cFos responses to opioid drugs in females’ nucleus accumbens (NAc) and basolateral amygdala (BLA), but not elsewhere. We further identify delta opioid receptors (DOR), which mature in the first week of life and thus later than kappa or mu opioid receptors, as a potential mediator of ELA's impacts on reward circuit functions. Accordingly, DOR mRNA in NAc was persistently reduced in adult females with ELA history. Moreover, pharmacological stimulation of NAc DORs increased opioid demand in control females (recapitulating the ELA phenotype), while blocking DORs in ELA females conversely reduced high-effort drug consumption, simulating the control rearing phenotype. These findings support a role for NAc DORs in mediating ELA-induced opioid vulnerability. In contrast, BLA neurons expressing DOR protein do not overlap heroin- responsive cells in ELA rats, arguing against a direct relationship of BLA DORs to heroin's addiction-relevant actions in the brain. Together, these results suggest a novel and selective role for NAc DORs in contributing to enduring, ELA-provoked vulnerability to OUD.

阿片类药物使用障碍（OUD）与早期生活逆境（ELA）有关，这种关联在女性中尤为强烈。我们曾在啮齿动物模型中发现，ELA 会有选择性地增加雌性阿片类药物成瘾的风险，但这种效应的机制尚不清楚。在这里，我们发现 ELA 能显著改变雌性大脑核（NAc）和基底外侧杏仁核（BLA）中的 cFos 对阿片类药物的反应，而其他部位则不会。我们进一步确定δ阿片受体（DOR）是ELA影响奖赏回路功能的潜在介质，它在出生后第一周成熟，因此晚于kappa或mu阿片受体。因此，在有ELA史的成年女性中，NAc中的DOR mRNA持续减少。此外，药物刺激NAc DORs会增加对照组雌鼠对阿片类药物的需求（重现ELA表型），而阻断ELA雌鼠体内的DORs则会减少高努力药物消耗，从而模拟对照组的饲养表型。这些发现支持 NAc DORs 在介导 ELA 诱导的阿片类物质易感性中的作用。与此相反，表达 DOR 蛋白的 BLA 神经元与 ELA 大鼠的海洛因反应细胞并不重叠，这表明 BLA DORs 与海洛因在大脑中的成瘾相关作用没有直接关系。总之，这些结果表明 NAc DORs 在导致 ELA 引起的对 OUD 的持久易感性方面发挥了新的选择性作用。

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