Transmembrane AMPA receptor regulatory protein TARP ɣ-8 is a target of ethanol that regulates self-administration and relapse in mice.

IF 3.3 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-07-18 DOI:10.1007/s00213-025-06848-1

Sara Faccidomo, Jessica L Hoffman, Julie Lee, Ciarra M Whindleton, Michelle Kim, Seth M Taylor, April Kim, Caroline Richter, Hanna L Seiters, Jacob M Bryant, Ashley Chang, Evan N Smith, Abigail E Agoglia, Susumu Tomita, Melissa A Herman, Clyde W Hodge

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引用次数: 0

Abstract

Background: Behavioral pathologies that characterize alcohol use disorder (AUD) are driven by the powerful reinforcing, or rewarding, properties of the drug. We have shown that glutamate AMPA receptor (AMPAR) activity is both necessary and sufficient for alcohol (ethanol) reinforcement. Transmembrane AMPAR regulatory protein (TARP) γ-8 is an essential auxiliary protein that regulates AMPAR expression and activity; however, the role of TARP ɣ-8 in AUD or other forms of addiction remains largely unexplored.

Objectives: This study investigated the mechanistic role of TARP γ-8 in operant ethanol self-administration (model of primary reinforcement) and cue-induced reinstatement of ethanol-seeking behavior (model of conditioned reinforcement) using TARP ɣ-8 heterozygous null ( ±) mice. To determine if TARP ɣ-8 signaling is targeted by ethanol use, we evaluated protein expression of TARP γ-8, GluA1, CaMKII, and PSD-95 following ethanol self-administration.

Results: A battery of tests evaluating food and water intake, taste preference, anxiety-like behavior, and object recognition memory showed no fundamental behavioral deficits in TARP γ-8 ( ±) mice, and no differences in response to acute ethanol or home-cage drinking as compared to wild-types. However, TARP γ-8 ( ±) mice exhibited significantly reduced acquisition and escalation of operant ethanol self-administration and reduced cue-induced reinstatement of ethanol-seeking behavior, with no differences in parallel sucrose-only controls. In wild-type mice, ethanol self-administration increased TARP γ-8 expression in the amygdala, nucleus accumbens, and hippocampus, and increased GluA1 expression in the amygdala and prefrontal cortex, compared to sucrose controls.

Conclusion: These findings highlight the specificity of TARP ɣ-8 regulation of ethanol reinforcement mechanisms and identify this crucial AMPAR auxiliary protein as a target of ethanol in reward-related brain regions, highlighting its potential for development of novel pharmacotherapies for AUD.

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跨膜AMPA受体调节蛋白TARP -8是乙醇调节小鼠自我给药和复发的靶标。

背景：以酒精使用障碍（AUD）为特征的行为病理学是由药物的强大强化或奖励特性驱动的。我们已经证明，谷氨酸AMPA受体（AMPAR）活性是酒精（乙醇）强化的必要和充分条件。跨膜AMPAR调节蛋白(TARP) γ-8是调节AMPAR表达和活性的重要辅助蛋白；然而，TARP -8在AUD或其他形式的成瘾中的作用仍未被探索。目的：研究TARP γ-8在操作性乙醇自我给药（初始强化模型）和线索诱导的乙醇寻求行为恢复（条件强化模型）中的作用机制。为了确定TARP γ-8信号是否被乙醇靶向，我们评估了自体给药后TARP γ-8、GluA1、CaMKII和PSD-95的蛋白表达。结果：一系列评估食物和水的摄入、味觉偏好、焦虑样行为和物体识别记忆的测试显示，TARP γ-8 （±）小鼠没有基本的行为缺陷，并且与野生型相比，对急性乙醇或家庭笼饮水的反应没有差异。然而，TARP γ-8 （±）小鼠表现出操作性乙醇自我给药的获取和升级，以及线索诱导的乙醇寻求行为的恢复，在平行蔗糖对照中没有差异。在野生型小鼠中，与蔗糖对照相比，乙醇自我给药增加了杏仁核、伏隔核和海马中TARP γ-8的表达，增加了杏仁核和前额叶皮层中GluA1的表达。结论：这些发现突出了TARP -8调节乙醇强化机制的特异性，并确定了这种关键的AMPAR辅助蛋白是乙醇在奖励相关脑区域的靶标，突出了其开发新型药物治疗AUD的潜力。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.