Pomrenze Matthew B, Vaillancourt Sam, Llorach Pierre, Rijsketic Daniel Ryskamp, Casey Austen B, Gregory Nicholas, Zhao Wesley, Girard Tyler E, Mattox Kathryn T, Salgado Juliana S, Malenka Robert C, Heifets Boris D
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California.
Biol Psychiatry. 2025 May 5. doi: 10.1016/j.biopsych.2025.04.020.
Ketamine has anesthetic, analgesic, and antidepressant properties, which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the brain regions and circuits that contribute to ketamine's antidepressant mechanism in humans.
We screened male and female wild-type mice for a behavioral response to ketamine that could be reversed by OR antagonists in several assays, including locomotor activation, analgesia, and the forced swim test. Whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, was used to identify brain areas that mediated ketamine/OR interactions. Region-specific pharmacological and genetic interference with μ OR (MOR) signaling was used to test predictions of whole-brain imaging results in a subset of behavioral assays.
Among a series of behavioral assays, only locomotor activation was sensitive to ketamine and blocked by an MOR-selective antagonist. Locomotor activation produced by the NMDA receptor antagonist MK-801 was not OR dependent. Whole-brain imaging revealed that cFos expression in neurons of the central amygdala (CeA) showed the greatest difference between ketamine in the presence versus absence of naltrexone. CeA neurons expressing both MOR and PKCδ were strongly activated by naltrexone, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine.
These data suggest that ketamine acts at MORs expressed in CeA neurons to produce acute hyperlocomotion.
氯胺酮具有麻醉、镇痛和抗抑郁特性，可能涉及多个神经调节系统。在人类中，阿片受体（OR）拮抗剂纳曲酮可阻断氯胺酮的抗抑郁作用。这一机制可能使氯胺酮有别于其他N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。反映氯胺酮OR依赖性行为效应的动物模型可能有助于揭示对氯胺酮在人类中的抗抑郁机制有贡献的脑区和神经回路。
我们在包括运动激活、镇痛和强迫游泳试验在内的多项试验中，筛选了雄性和雌性野生型小鼠对氯胺酮的行为反应，这些反应可被OR拮抗剂逆转。对用纳曲酮或赋形剂预处理的氯胺酮处理小鼠进行cFos表达的全脑成像，以识别介导氯胺酮/OR相互作用的脑区。对μ阿片受体（MOR）信号进行区域特异性药理学和基因干扰，以在一部分行为试验中检验全脑成像结果的预测。
在一系列行为试验中，只有运动激活对氯胺酮敏感并被MOR选择性拮抗剂阻断。NMDA受体拮抗剂MK-801产生的运动激活不依赖于OR。全脑成像显示，在存在与不存在纳曲酮的情况下，中央杏仁核（CeA）神经元中的cFos表达差异最大。同时表达MOR和蛋白激酶Cδ（PKCδ）的CeA神经元被纳曲酮强烈激活，并且在CeA中通过药理学或遗传学方法选择性中断MOR功能可阻断氯胺酮的运动效应。
这些数据表明，氯胺酮作用于CeA神经元中表达的MOR以产生急性运动亢进。
