Background: Premenstrual dysphoric disorder (PMDD) is high in women of childbearing age with obvious premenstrual irritability. However, reliable animal models are still lacking.

Materials and Methods: PMDD rat model of premenstrual irritability was induced by the resident-intruder paradigm (RIP). Behavioral characteristics were determined by the aggressive behavior test, elevated plus maze, open-field test, and breast width measurement. The estrous cycle in rats was artificially manipulated by bilateral ovariectomy and exogenous hormone injection to verify the model phenotype’s dependence on the estrous cycle.

Fluoxetine and Baixiangdan capsules were administered by gavage to determine the symptom improvement effect of PMDD irritability. Biomarkers in serum and brain were detected using ELISA, and GABRA4 was detected in the brain by RT-PCR and Western blot.

Results: Rat models demonstrated similar clinical characteristics as PMDD, such as premenstrual irritability and anxiety, and the above symptoms were estrous cycle-dependent. In addition, the levels of progesterone (P) and ALLO hormones decreased in the serum, hippocampus, amygdala, and frontal lobe in the NR phase. The contents of 5-HT in the brain were significantly increased, while NE and GABA contents were considerably reduced. Moreover, mRNA and protein expression of GABRA4 levels in model rats’ amygdala, hippocampus, and frontal lobe were significantly increased, while drug intervention downregulated its expression in these tissues.

Conclusion: Premenstrual irritability rat model of PMDD demonstrates a behavioral phenotype consistent with the clinical symptoms of PMDD and micro index. The increased levels of 5-HT, NE, and expression of GABRA4, as well as the decrease of GABA, P, and ALLO levels, may be critical biomarkers of the abnormal changes that occur during the pathogenesis of PMDD.