Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy.
Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185, Rome, Italy.
Behav Brain Res. 2021 Jun 25;408:113256. doi: 10.1016/j.bbr.2021.113256. Epub 2021 Mar 26.
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder. It has been recently proposed that these drugs, by enhancing neural plasticity, amplify the influences of the living conditions on mood. Consequently, SSRI outcome depends on the quality of the environment, improving symptomatology mainly in individuals living in favorable conditions. In adverse conditions, drugs with a different mechanism of action might have higher efficacy. The antibiotic minocycline, with neuroprotective and anti-inflammatory properties, has been recently proposed as a novel potential antidepressant treatment. To explore the drug-by-environment interaction, we compared the effects on depressive-like behavior and neural plasticity of the SSRI fluoxetine and minocycline in enriched and stressful conditions. We first exposed C57BL/6 adult female mice to 14 days of chronic unpredictable mild stress to induce a depressive-like profile. Afterward, mice received vehicle, fluoxetine, or minocycline for 21 days, while exposed to either enriched or stressful conditions. During the first five days, fluoxetine led to an improvement in enrichment but not in stress. By contrast, minocycline led to an improvement in both conditions. After 21 days, all groups showed a significant improvement in enrichment while fluoxetine worsened the depressive like behavior in stress. The effects of the drugs on neural plasticity, measured as long-term potentiation, were also environment-dependent. Overall, we show that the environment affects fluoxetine but not minocycline outcome, indicating that the latter represents a potential alternative to SSRIs to treat depressed patients living in adverse conditions. From a translation perspective, our finding call for considering the drug-by-environment interaction to select the most effective pharmacological treatment.
选择性 5-羟色胺再摄取抑制剂（SSRIs）是治疗重度抑郁症的一线药物。最近有人提出，这些药物通过增强神经可塑性，放大了生活条件对情绪的影响。因此，SSRIs 的疗效取决于环境的质量，主要改善生活在有利条件下的个体的症状。在不利条件下，具有不同作用机制的药物可能具有更高的疗效。具有神经保护和抗炎特性的抗生素米诺环素最近被提议作为一种新的潜在抗抑郁治疗方法。为了探索药物-环境相互作用，我们比较了 SSRI 氟西汀和米诺环素在丰富和应激环境中的抗抑郁样行为和神经可塑性的影响。我们首先使 C57BL/6 成年雌性小鼠暴露于 14 天的慢性不可预测的轻度应激中，以诱导出抑郁样表型。之后，小鼠在暴露于丰富或应激环境的同时，接受载体、氟西汀或米诺环素治疗 21 天。在最初的五天里，氟西汀改善了丰富环境，但没有改善应激环境。相比之下，米诺环素改善了两种环境。21 天后，所有组在丰富环境中都有明显改善，而氟西汀在应激中加重了抑郁样行为。药物对神经可塑性的影响，如长时程增强，也取决于环境。总的来说，我们表明环境影响氟西汀但不影响米诺环素的疗效，这表明后者是治疗生活在不利环境中的抑郁患者的 SSRI 的潜在替代药物。从翻译的角度来看，我们的发现呼吁考虑药物-环境相互作用，以选择最有效的药物治疗。
