Abstract: Premenstrual dysphoric disorder (PMDD), a subtype of premenstrual syndrome (PMS), involves physical and emotional symptoms that impact patients’ daily lives and productivity. A reliable, side-effect-free clinical intervention is needed. Shuyu capsule is an effective traditional Chinese medicine preparation for PMDD used in the clinics, but its therapeutic mechanism remains unclear. Previous research has suggested that the γ-aminobutyric acidergic (GABAergic) system in the periaqueductal gray (PAG) may play a role in treating PMDD with traditional Chinese medicine, but there is a lack of functional verification. This study aims to reveal the potential mechanism of the Shuyu capsule in treating PMDD. The study employed an experimental design using female C57BL/6J and Vgat-Cre mice to assess the effects of Shuyu capsules on PMDD, with a focus on the GABAergic system in the dorsal PAG (dPAG). Assessments were conducted using the forced swimming test (FST) to gauge depression-like behaviors and western blot (WB) and immunofluorescence (IF) to measure the numbers of active GABAergic neurons and the γ-aminobutyric acid type A receptor (GABA_AR) δ subunit (GABRD) expression. Chemogenetic techniques and adeno-associated virus were specifically used to activate GABAergic neurons and knock down the expression of subunits, respectively, providing insights into the neurobiological mechanisms underpinning the therapeutic effects of Shuyu capsules in treating PMDD. After being stressed by FST, the immobility duration of PMDD mice in the late dioestrus (LD) phase decreased after the Shuyu capsule intervention, implying that it can improve the estrous cycle-dependent depression-like phenotype in PMDD mice. Additionally, the application of Shuyu capsule can downregulate the expression of GABRD and reverse the downtrend of activated GABAergic neurons in the dPAG of PMDD model mice. We also found that single-target manipulation was enough to improve the depression-like behavior of PMDD model mice. Transgenic mice with GABRD knockout were established, and their behaviors were tested, revealing changes in their exploratory behaviors, indicating that the GABRD may be closely related to anxiety disorders. Shuyu capsule plays an anti-PMDD role by activating GABAergic neurons and downregulating the expression of GABRD in the dPAG. This provides a theoretical basis for the clinical treatment of PMDD with traditional Chinese medicine and promotes the development of drugs for treating PMDD.

Key words: Premenstrual dysphoric disorder; Periaqueductal gray; γ-Aminobutyric acidergic (GABAergic) neuron; γ-Aminobutyric acid receptor δ subunit (GABRD); Shuyu capsule; Depression-like behavior

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