Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychiatry and Behavioral Neurosciences, Tampa, FL, USA.
College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA, USA.
Neuropharmacology. 2023 May 1;228:109457. doi: 10.1016/j.neuropharm.2023.109457. Epub 2023 Feb 9.
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 neuron Oprk1 (KOR gene) in excessive alcohol consumption, negative emotional state, and executive function. To do so, Oprk1 mRNA 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 of Oprk1 in VTA DA neurons. The effect of this overexpression was evaluated on operant alcohol self-administration, negative emotional states, and executive function. We found that VTA Oprk1 overexpression recapitulates some phenotypes of alcohol dependence including escalated alcohol self-administration and depressive-like behavior. However, working memory performance was not impacted following VTA Oprk1 overexpression 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 understanding Oprk1-mediated contributions to alcohol use disorder (AUD) should be an important future goal.
内啡肽（DYN）/κ-阿片受体（KOR）系统参与情绪低落和负性情绪状态。KOR 功能失调会促进与酒精依赖相关的戒断期适应性行为调节障碍。腹侧被盖区（VTA）的中脑边缘多巴胺（DA）投射支配扩展的杏仁核回路，突触前 KOR 减弱这些区域的 DA，导致过度饮酒和负性情感样行为，而中脑皮质 KOR 调节的 DA 投射与执行功能和决策有关。因此，DYN/KOR 系统的神经适应是考虑开发个性化治疗方案的重要方面。在此，我们研究了 VTA DA 神经元 Oprk1（KOR 基因）在过度饮酒、负性情绪和执行功能中的作用。为此，我们对 Oprk1 mRNA 表达和 KOR 功能进行了特征分析，以确认 VTA 中酒精依赖诱导的失调。然后，使用转基因 Cre-Lox 大鼠模型（雄性和雌性 TH::Cre 大鼠）允许在 VTA DA 神经元中条件性和诱导性过表达 Oprk1。评估这种过表达对操作性酒精自我给药、负性情绪状态和执行功能的影响。我们发现，VTA Oprk1 的过表达再现了一些酒精依赖的表型，包括酒精自我给药增加和抑郁样行为。然而，在 TH::Cre 大鼠中 VTA Oprk1 过表达后，工作记忆性能不受影响。这支持了这样的假设，即中脑边缘 DA 系统中 KOR 信号的失调是酒精依赖症状的重要贡献者，并表明理解 Oprk1 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。
