Rizzo Arianna, Garçon-Poca Maria Zelai, Essmann Amelie, Souza Adriana Jesus, Michaelides Michael, Ciruela Francisco, Bonaventura Jordi
Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
Mol Psychiatry. 2025 Feb 19. doi: 10.1038/s41380-025-02931-3.
Esketamine represents a new class of drugs for treating mood disorders. Unlike traditional monoaminergic-based therapies, esketamine primarily targets N-methyl-D-aspartate receptors (NMDAR). However, esketamine is a complex drug with low affinity for NMDAR and can also bind to other targets, such as opioid receptors. Its precise mechanism of action for its antidepressant properties remains debated, as does its potential for misuse. A key component at the intersection of mood and reward processing is the dopaminergic system. In this study, we evaluated the effects of esketamine in locomotion, anxiety tests and operant responding and we used in vivo fiber photometry to explore the neurochemical effects of esketamine in the nucleus accumbens of mice. Our findings demonstrated multifaceted effects of esketamine on neurotransmitter dynamics. In freely behaving mice, esketamine increased locomotion and increased extracellular dopamine tone -by impairing dopamine clearance rather than promoting dopamine release- while decreasing glutamatergic activity. However, it decreased dopamine spontaneous release event frequency and impaired reward-evoked dopamine release, leading to a reduction in operant responding rates. These dopaminergic effects were partially, and conditionally, blocked by the opioid antagonist naloxone and required glutamatergic input. In summary, our study reveals a complex interaction between neurotransmitter systems, suggesting that the neurochemical effects of esketamine are both circuit- and state-dependent.
艾氯胺酮是一类用于治疗情绪障碍的新型药物。与传统的基于单胺能的疗法不同，艾氯胺酮主要作用于N-甲基-D-天冬氨酸受体（NMDAR）。然而，艾氯胺酮是一种对NMDAR亲和力较低的复杂药物，它还能与其他靶点结合，如阿片受体。其抗抑郁特性的确切作用机制以及潜在的滥用可能性仍存在争议。情绪和奖赏处理交叉点的一个关键组成部分是多巴胺能系统。在本研究中，我们评估了艾氯胺酮在运动、焦虑测试和操作性反应方面的作用，并使用体内光纤光度法探究艾氯胺酮对小鼠伏隔核的神经化学影响。我们的研究结果表明艾氯胺酮对神经递质动力学具有多方面的影响。在自由活动的小鼠中，艾氯胺酮通过损害多巴胺清除而非促进多巴胺释放来增加运动并提高细胞外多巴胺水平，同时降低谷氨酸能活性。然而，它降低了多巴胺自发释放事件的频率，并损害了奖赏诱发的多巴胺释放，导致操作性反应率降低。这些多巴胺能效应部分地且有条件地被阿片受体拮抗剂纳洛酮阻断，并且需要谷氨酸能输入。总之，我们的研究揭示了神经递质系统之间的复杂相互作用，表明艾氯胺酮的神经化学效应既依赖于神经回路，也依赖于机体状态。
