Mayer Felix P, Stewart Adele, Varman Durairaj Ragu, Moritz Amy E, Foster James D, Owens Anthony W, Areal Lorena B, Gowrishankar Raajaram, Velez Michelle, Wickham Kyria, Phelps Hannah, Katamish Rania, Rabil Maximilian, Jayanthi Lankupalle D, Vaughan Roxanne A, Daws Lynette C, Blakely Randy D, Ramamoorthy Sammanda
Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, USA.
Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, USA.
Mol Psychiatry. 2025 May 29. doi: 10.1038/s41380-025-03055-4.
Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate, as exemplified by the therapeutic use of d-amphetamine and methylphenidate for the treatment of ADHD, agents with high abuse liability. In search for an improved and non-addictive therapeutic approach for the treatment of DA-linked disorders, we utilized a preclinical mouse model expressing the human DA transporter (DAT) coding variant DAT Val559, previously identified in individuals with ADHD, ASD, or BPD. DAT Val559, like several other disease-associated variants of DAT, exhibits anomalous DA efflux (ADE) that can be blocked by d-amphetamine and methylphenidate. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might also provide an alternative approach to normalizing DA-signaling disrupted by perturbed DAT function. Here we demonstrate that KOR stimulation leads to enhanced surface trafficking and phosphorylation of Thr53 in wildtype DAT, effects achieved constitutively by the Val559 mutant. Moreover, these effects can be rescued by KOR antagonism of DAT Val559 in ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release as well as sex-dependent behavioral abnormalities observed in DAT Val559 mice. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.
异常的多巴胺（DA）信号传导与精神分裂症、双相情感障碍（BPD）、自闭症谱系障碍（ASD）、物质使用障碍和注意力缺陷多动障碍（ADHD）有关。这些疾病的治疗仍然不足，以用于治疗ADHD的右旋苯丙胺和哌甲酯的治疗为例，这些药物具有很高的滥用可能性。为了寻找一种改进的、无成瘾性的治疗方法来治疗与DA相关的疾病，我们利用了一种临床前小鼠模型，该模型表达人类DA转运体（DAT）编码变体DAT Val559，该变体先前在患有ADHD、ASD或BPD的个体中被鉴定出来。与DAT的其他几种与疾病相关的变体一样，DAT Val559表现出异常的DA流出（ADE），可以被右旋苯丙胺和哌甲酯阻断。κ阿片受体（KORs）由DA神经元表达并调节DA的释放和清除，这表明靶向KORs也可能提供一种使因DAT功能紊乱而破坏的DA信号正常化的替代方法。在这里，我们证明KOR刺激导致野生型DAT的表面转运增强和Thr53磷酸化，而Val559突变体则组成性地实现了这些效应。此外，在体外实验中，KOR对DAT Val559的拮抗作用可以挽救这些效应。重要的是，KOR拮抗作用还纠正了体内DA释放以及在DAT Val559小鼠中观察到的性别依赖性行为异常。鉴于其低滥用可能性，我们对人类DA相关疾病的有效构建模型的研究强化了将KOR拮抗作为治疗DA相关脑部疾病的药理学策略的考虑。
