Sex-based changes in rat brain serotonin and behavior in a model of altitude-related vulnerability to treatment-resistant depression

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.