9-cis-13,14-dihydroretinoic acid (9CDHRA), acts as an endogenous ligand of the retinoid X receptors (RXRs), and is an active form of a suggested new vitamin, vitamin A5/X. Nutritional-relevance of this pathway as well as its detailed role in vertebrate physiology, remain largely unknown. Since recent GWAS data and experimental studies associated RXR-mediated signaling with depression, we explored here the relevance of RXR and vitamin A5/X-mediated signaling in the control of stress adaptation and depressive-like behaviors in mice. We found that compromised availability of 9CDHRA in Rbp1−/− mice was associated with increased despair in the forced swim and anhedonia in the sucrose preference test. 9CDHRA similarly to synthetic RXR agonist, BMS649, normalized despair behaviors in Rbp1−/− but not Rxrγ−/− mice, supporting involvement of RXR signaling in anti-despair activity of these ligands. Importantly, similarly to BMS649, the 9CDHRA and its nutritional-precursor, 9-cis-13,14-dihydroretinol (vitamin A5/X alcohol), prevented development of depressive-like behaviors in mice exposed to chronic social defeat stress, revealing the beneficial role of RXRs and its endogenous ligand in stress adaptation process. These data point to the need for relevant nutritional, biochemical and pharmacological studies of this signaling pathway in human, both in physiological conditions and in pathologies of stress-related disorders.

9-顺式-13,14-二氢视黄酸 (9CDHRA) 作为类视黄醇 X 受体 (RXR) 的内源性配体，是一种建议的新维生素维生素 A5/X 的活性形式。该途径的营养相关性及其在脊椎动物生理学中的详细作用，在很大程度上仍然未知。由于最近的 GWAS 数据和实验研究将 RXR 介导的信号传导与抑郁症相关联，我们在这里探讨了 RXR 和维生素 A5/X 介导的信号传导在控制小鼠应激适应和抑郁样行为中的相关性。我们发现Rbp1-/-小鼠中9CDHRA 的可用性受损与强迫游泳中的绝望增加和蔗糖偏好测试中的快感缺乏有关。9CDHRA 与合成 RXR 激动剂 BMS649 相似，在Rbp1-/-但不是Rxrγ-/-小鼠，支持 RXR 信号参与这些配体的抗绝望活性。重要的是，与 BMS649 类似，9CDHRA 及其营养前体 9-顺式-13,14-二氢视黄醇（维生素 A5/X 酒精）可防止暴露于慢性社交失败压力的小鼠出现抑郁样行为，揭示了有益的RXRs 及其内源性配体在应激适应过程中的作用。这些数据表明需要对人类的这一信号通路进行相关的营养、生化和药理学研究，无论是在生理条件下还是在压力相关疾病的病理学中。