School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, Bristol BS8 1TD, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB3 2DY, UK.
Sci Transl Med. 2024 Jan 10;16(729):eadi2403. doi: 10.1126/scitranslmed.adi2403.
How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model.
快速作用抗抑郁药（RAADs），如氯胺酮，如何在重度抑郁症（MDD）患者中立即和持续改善情绪状态，目前还知之甚少。MDD 的一个核心特征是与消极情绪状态相关的认知加工偏见的普遍性，减轻消极情绪偏见可能是对药物治疗反应的一个指标。在这里，我们使用了基于联想学习任务的大鼠情感偏见行为测试来研究 RAAD 的作用。为了产生情感偏见，动物学会了在存在或不存在情感状态操作的情况下将两种不同的挖掘基质与食物奖励相关联。在两种奖励相关的挖掘基质之间进行选择，以量化产生的情感偏见。RAAD 氯胺酮、东莨菪碱或裸盖菇素的急性治疗选择性地减弱了情感偏见测试中的负性情感偏见。低剂量但不是高剂量的氯胺酮和裸盖菇素在 RAAD 治疗后 24 小时逆转了负性情感偏见的效价。只有裸盖菇素治疗，而不是氯胺酮或东莨菪碱治疗，导致了一种积极的情感偏见，这种偏见依赖于新的学习和记忆形成。氯胺酮的再学习效应依赖于大鼠内侧前额叶皮层的蛋白质合成，并且可以通过线索重新激活来调节，这与经验依赖性神经可塑性一致。这些发现表明了一种神经心理学机制，可能解释了 RAAD 的急性和持续作用，可能将它们对神经可塑性的影响与啮齿动物模型中的情感偏见调节联系起来。
