Recapitulating phenotypes of alcohol dependence via overexpression of Oprk1 in the ventral tegmental area of non-dependent TH::Cre rats.
Recapitulating phenotypes of alcohol dependence via overexpression of Oprk1 in the ventral tegmental area of non-dependent TH::Cre rats.
复制标题
通过在非依赖性 TH::Cre 大鼠腹侧被盖区过度表达 Oprk1 来概括酒精依赖性表型。
DOI：
10.1016/j.neuropharm.2023.109457
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发表时间：
2023
影响因子：
4.7
通讯作者：
Walker,BrendanM
中科院分区：
文献类型：
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作者：
Lepreux,Gaetan;Shinn,GraceE;Wei,Gengze;Suko,Azra;Concepcion,George;Sirohi,Sunil;SoonGo,Bok;Bruchas,MichaelR;Walker,BrendanM
强啡肽（DYN）/κ-阿片受体（KOR）系统参与烦躁不安和负面情绪状态。KOR功能失调促进了酒精依赖戒断过程中的适应不良行为调节。腹侧被盖区（VTA）的中脑边缘多巴胺（DA）投射支配杏仁核的延伸回路，突触前KORs减弱这些区域的DA，导致过度饮酒和负性情感样行为，而中皮层KORs调节的DA投射与执行功能和决策有关。因此，DYN/KOR系统中发生的神经适应是开发个性化治疗解决方案需要考虑的重要方面。在此，我们研究VTA DA neuronOprk 1（KOR基因）在过度饮酒，消极情绪状态和执行功能中的作用。为此，Oprk 1 mRNA表达和KOR功能的特点，以确认酒精依赖诱导的VTA失调。然后，使用转基因Cre-Lox大鼠模型（雄性和雌性TH：：Cre大鼠）来允许Oprk 1在腹侧被盖区DA神经元中的条件性和诱导性过表达。这种过度表达的影响进行了评估，操作性酒精自我管理，消极情绪状态，和执行功能。我们发现VTAOprk 1过表达再现了酒精依赖的一些表型，包括酒精自我给药和抑郁样行为。然而，TH：：Cre大鼠中VTAOprk 1过表达后，工作记忆表现没有受到影响。这支持了这一假设，即中脑边缘DA系统内失调的KOR信号是酒精依赖症状的重要贡献者，并表明理解Oprk 1介导的对酒精使用障碍（AUD）的贡献应该是一个重要的未来目标。
The dynorphin (DYN)/kappa-opioid receptor (KOR) system is involved in dysphoria and negative emotional states. Dysregulation of KOR function promotes maladaptive behavioral regulation during withdrawal associated with alcohol dependence. Mesolimbic dopaminergic (DA) projections from the ventral tegmental area (VTA) innervate the extended amygdala circuitry and presynaptic KORs attenuate DA in these regions leading to an excessive alcohol consumption and negative affective-like behavior, whereas mesocortical KOR-regulated DA projections have been implicated in executive function and decision-making. Thus, the neuroadaptations occurring in DYN/KOR systems are important aspects to consider for the development of personalized therapeutic solutions. Herein, we study the contribution of the VTA DA neuronOprk1(KOR gene) in excessive alcohol consumption, negative emotional state, and executive function. To do so,Oprk1mRNA expression and KOR function were characterized to confirm alcohol dependence-induced dysregulation in the VTA. Then, a transgenic Cre-Lox rat model (male and female TH::Cre rats) was used to allow for conditional and inducible overexpression ofOprk1in VTA DA neurons. The effect of this overexpression was evaluated on operant alcohol self-administration, negative emotional states, and executive function. We found that VTAOprk1overexpression recapitulates some phenotypes of alcohol dependence including escalated alcohol self-administration and depressive-like behavior. However, working memory performance was not impacted following VTAOprk1overexpression in TH::Cre rats. This supports the hypothesis that dysregulated KOR signaling within the mesolimbic DA system is an important contributor to symptoms of alcohol dependence and shows that understandingOprk1-mediated contributions to alcohol use disorder (AUD) should be an important future goal.