Rationale

Rates of depression and suicide increase with altitude. In our animal model, rats housed at moderate altitude vs. at sea level exhibit increased depressive symptoms in the forced swim test (FST) and lack of response to selective serotonin reuptake inhibitors (SSRIs). Depression and SSRI resistance are linked to disrupted serotonergic function, and hypobaric hypoxia may reduce the oxygen-dependent synthesis of serotonin. We therefore tested brain serotonin in rats housed at altitude.

Methods

Sprague–Dawley rats were housed at altitude (4,500 ft, 10,000 ft) vs. sea level for 7–36 days. Brain serotonin was measured by ELISA, or behavior evaluated in the FST, sucrose preference (SPT), or open-field tests (OFT).

Results

After 2 weeks at 4,500 ft or 10,000ft vs. sea level, serotonin levels decreased significantly at altitude in the female prefrontal cortex, striatum, hippocampus, and brainstem, but increased with altitude in the male hippocampus and brainstem. Female brain serotonin decreased from 7 to 36 days at 4,500 ft, but males did not vary. At 2 weeks and 24 days, females at altitude exhibit lower brain serotonin and increased depressive symptoms in the FST and SPT, with motor behavior unaltered. In males, serotonin, passive coping in the FST and OFT immobility increased with altitude at 2 weeks, but not at 24 days. Male SPT behavior did not change with altitude.

Conclusions

Females may be more vulnerable to depressive symptoms at altitude, while males may be resilient. Chronic hypoxic stress at altitudes as low as 4,500 ft may cause a brain serotonin imbalance to worsen vulnerability to depression and SSRI resistance, and potentially worsen suicide risk.

中文翻译：

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海拔相关易感性抑郁症模型中大鼠脑血清素和行为的性别变化

基本原理

抑郁症和自杀率随海拔升高而增加。在我们的动物模型中，与海平面相比，饲养在中等海拔的大鼠在强迫游泳试验 (FST) 中表现出更多的抑郁症状，并且对选择性 5-羟色胺再摄取抑制剂 (SSRI) 缺乏反应。抑郁症和 SSRI 抵抗与血清素功能受损有关，低压缺氧可能会减少血清素的氧依赖性合成。因此，我们在高海拔饲养的大鼠中测试了大脑血清素。

方法

Sprague-Dawley 大鼠在海拔（4,500 英尺、10,000 英尺）相对于海平面的情况下饲养 7-36 天。脑血清素通过 ELISA 测量，或在 FST、蔗糖偏好 (SPT) 或开放场测试 (OFT) 中评估的行为。

结果

在 4,500 英尺或 10,000 英尺（相对于海平面）2 周后，女性前额叶皮层、纹状体、海马和脑干的血清素水平在海拔高度显着下降，但男性海马和脑干的血清素水平随海拔升高而增加。在 4,500 英尺处，雌性大脑血清素从 7 天减少到 36 天，但雄性没有变化。在 2 周和 24 天时，高海拔雌性表现出较低的脑血清素和 FST 和 SPT 中的抑郁症状增加，运动行为未改变。在男性中，血清素、FST 中的被动应对和 OFT 不动在 2 周随海拔升高而增加，但在 24 天时没有增加。雄性 SPT 行为不随海拔变化。

结论

女性在高海拔地区可能更容易出现抑郁症状，而男性可能有弹性。海拔低至 4,500 英尺的慢性缺氧压力可能会导致大脑血清素失衡，从而加剧对抑郁症和 SSRI 抵抗的脆弱性，并可能增加自杀风险。