Ottawa Hospital Research Institute (Neuroscience), University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H 8M5, Canada.
J Neurosci. 2019 Feb 20;39(8):1334-1346. doi: 10.1523/JNEUROSCI.0352-18.2018. Epub 2018 Dec 14.
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons () were tested for response to SSRIs. Tamoxifen-induced recombination in adult mice specifically reduced 5-HT1A autoreceptor levels. The mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type () mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of but not mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB cells were quantified. FosB cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of mice, suggesting increased raphe activation. In but not mice, FLX reduced FosB cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment. Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response.
选择性 5-羟色胺（5-HT）再摄取抑制剂（SSRIs）是一线抗抑郁药，但需要数周时间才能发挥作用。慢性 SSRI 治疗会导致 5-HT1A 自身受体脱敏，从而增强 5-HT 神经传递。成年 5-HT 神经元中 5-HT1A 自身受体基因缺失的小鼠（雌雄均可）被测试对 SSRIs 的反应。他莫昔芬诱导成年 小鼠中的重组特异性降低 5-HT1A 自身受体水平。 小鼠表现出 5-HT1A 自身受体介导的体温过低和电生理反应丧失，但焦虑或抑郁样行为无变化。亚慢性氟西汀（FLX）治疗在新奇抑制喂养和高架十字迷宫试验中对 小鼠引起意外的焦虑效应，依地普仑在新奇抑制喂养试验中也引起这种效应。在野生型（）小鼠中未见这种作用。亚慢性 FLX 增加前额叶皮层、海马和中缝背核 5-HT 代谢，但 小鼠未见这种作用，提示 5-HT 释放过度激活。为了检测慢性细胞激活，对 FosB 细胞进行了定量。 小鼠的海马 CA2/3 和中缝背核 5-HT 细胞中 FosB 细胞减少，而 小鼠的中缝背核 5-HT 细胞中 FosB 细胞增加，提示中缝背核激活增加。在 但不是 小鼠中，FLX 减少中缝核、海马、海马和中隔的 FosB 细胞，这些部位接受丰富的 5-HT 投射。因此，在没有 5-HT1A 自身受体的情况下，SSRIs 会引起矛盾的焦虑反应。这可能涉及到背侧和中缝核激活的不平衡，以调节隔海马或穹窿伞状纤维通路。这些结果表明，5-HT1A 自身受体的明显减少可能为 SSRI 治疗反应异常提供一个标志物。选择性 5-羟色胺再摄取抑制剂（SSRIs）在人类和小鼠模型中有效治疗焦虑和抑郁。然而，在某些情况下，SSRIs 会增加焦虑，但涉及的机制尚不清楚。在这里，我们表明，成年期敲除（KO）5-HT1A 自身受体（一种关键的 5-HT 活性负调节因子），而不是增强 SSRI 的益处，会导致 SSRI 诱导的焦虑效应，这似乎涉及到某些脑区 5-HT 系统的过度激活。因此，5-HT1A 自身受体水平非常低的个体，如儿童或青少年，可能有发生 SSRI 诱导的焦虑反应的风险。
