Brain α2-containing GABA_A receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of α2-containing GABA_A receptors following chronic social defeat stress using male mice deficient in the α2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the α2 subunit on intermediates of the glutathione synthesis pathway. We found that α2-containing GABA_A receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of α2-containing GABA_A receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light–dark box, and novel open field tests. Increases in indices of oxidative stress—reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios—were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking α2-containing GABA_A receptors. We conclude that α2-containing GABA_A receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that α2-containing GABA_A receptors provide against oxidative stress in NAc and the prefrontal cortex.

大脑中含有 α2 的 GABA _A受体在调节焦虑和恐惧样行为中发挥着关键作用。然而，目前尚不清楚这些受体是否也在调节慢性压力的恢复能力方面发挥作用，以及在哪些大脑区域和细胞类型中介导这种作用。我们使用在表达多巴胺 D1 或 D2 受体的神经元（例如伏隔核（NAc）内）中全局或有条件地缺乏 α2 亚基的雄性小鼠，评估了含有 α2 的 GABA _A受体在慢性社会失败压力后的作用。此外，我们还研究了缺乏 α2 亚基对谷胱甘肽合成途径中间体的影响。我们发现，D2 受体阳性神经元上的含 α2 GABA _A受体（而非 D1 受体阳性神经元上）可促进对慢性社交失败压力的恢复能力，如社交互动测试中所反映的那样。含 α2 的 GABA _A受体对 D2 受体阳性神经元的促弹性作用似乎与焦虑样行为的改变没有直接关系，如高架十字迷宫、明暗盒和新颖的实验所反映的那样。旷场测试。在缺乏含 α2 的 GABA _A受体的小鼠的 NAc 和前额皮质中，但在海马中没有发现氧化应激指数的增加（表现为胱硫醚水平的增加和 GSH/GSSG 比率的降低）。我们得出的结论是，特定大脑区域和细胞群中含有 α2 的 GABA _A受体可促进压力恢复能力，独立于对焦虑样行为的直接影响。 导致这种弹性增强的一个潜在机制是含有 α2 的 GABA _A受体针对 NAc 和前额皮质的氧化应激提供保护。