Stress vulnerability and pathogenic mechanisms in stress-related disorders are strongly associated with the functions of serotonin transporter (SERT). SERT phosphorylation induces a reduction of the serotonin (5-HT, 5-hydroxytryptamine) transport properties, its phosphorylation regulated by protein kinase C (PKC). However, the functional relationship between regulated SERT activity by PKC and stress vulnerability remains unclear. Here, we investigated whether the functional regulation of SERT by PKC was involved in stress vulnerability using mice exposed to twice-swim stress that exhibited the impairment of social behaviors. The mild-swim stress (6 min) given just before the social interaction test did not affect the social behaviors of mice. However, mice exposed to strong-swim stress (15 min) became vulnerable to the mild-swim stress, and subsequent social behaviors were impaired. Chelerythrine, a PKC inhibitor, exacerbated decreased sociality in mice exposed to acute mild-swim stress. Phorbol 12-myristate 13-acetate (PMA), a PKC activator, ameliorated the impairment of social behaviors in mice exposed to twice-swim stress. Phosphorylated PKCβI or SERT and 5-HT levels were decreased in the prefrontal cortex of twice-stressed mice. These decreases were attenuated by PMA. Our findings demonstrate that mice exposed to twice-swim stress developed stress vulnerability, which may be involved in the regulation of SERT phosphorylation and 5-HT levels accompanying PKCβI activity.

压力相关疾病的压力易感性和致病机制与血清素转运蛋白 (SERT) 的功能密切相关。SERT 磷酸化诱导血清素（5-HT、5-羟色胺）转运特性的降低，其磷酸化受蛋白激酶 C (PKC) 调节。然而，PKC 调节的 SERT 活性与应激脆弱性之间的功能关系仍不清楚。在这里，我们研究了 PKC 对 SERT 的功能调节是否涉及使用暴露于两次游泳压力的小鼠的应激脆弱性，这些小鼠表现出社会行为的损害。在社交互动测试之前给予的温和游泳压力（6分钟）不会影响小鼠的社交行为。然而，暴露于强游泳压力（15分钟）的小鼠变得容易受到轻度游泳压力，随后的社会行为受到损害。白屈菜红碱是一种 PKC 抑制剂，加剧了暴露于急性轻度游泳压力的小鼠的社交能力下降。Phorbol 12-myristate 13-acetate (PMA) 是一种 PKC 激活剂，可改善暴露于两次游泳压力的小鼠的社会行为障碍。二次应激小鼠前额叶皮层的磷酸化 PKCβI 或 SERT 和 5-HT 水平降低。PMA 减弱了这些下降。我们的研究结果表明，暴露于两次游泳压力的小鼠会出现压力脆弱性，这可能与伴随 PKCβI 活性的 SERT 磷酸化和 5-HT 水平的调节有关。改善了暴露于两次游泳压力的小鼠的社会行为障碍。二次应激小鼠前额叶皮层的磷酸化 PKCβI 或 SERT 和 5-HT 水平降低。PMA 减弱了这些下降。我们的研究结果表明，暴露于两次游泳压力的小鼠会出现压力脆弱性，这可能与伴随 PKCβI 活性的 SERT 磷酸化和 5-HT 水平的调节有关。改善了暴露于两次游泳压力的小鼠的社会行为障碍。二次应激小鼠前额叶皮层的磷酸化 PKCβI 或 SERT 和 5-HT 水平降低。PMA 减弱了这些下降。我们的研究结果表明，暴露于两次游泳压力的小鼠会出现压力脆弱性，这可能与伴随 PKCβI 活性的 SERT 磷酸化和 5-HT 水平的调节有关。