The WAG/Rij Rat Model of Depression Comorbid with Absence Epilepsy: Sex Differences and Neurochemical Mechanisms

Depression is the most common psychiatric disorder and is frequently comorbid with epilepsy. Despite the high incidence of depression in epilepsy and the well-established sex differences in depression in clinical studies, sex differences in depression in epilepsy models remain unclear. This study aimed to investigate sex differences in depression comorbid with absence epilepsy and their neurochemical mechanisms in the WAG/Rij rat model. WAG/Rij rats, regardless of sex, exhibited symptoms of depression-like behaviour in the forced swimming test: increased immobility and decreased climbing, swimming, and diving. Both strain and sex differences were found in sucrose preference and splash tests, indicating anhedonia. However, anhedonia was more pronounced in WAG/Rij females compared to males. Unlike the males, WAG/Rij females showed signs of increased anxiety, suggesting an anxious depression phenotype. In WAG/Rij rats compared to Wistar controls, a reduced content of dopamine and its metabolites in brain structures was revealed, indicating a reduced dopaminergic tone of the brain. In WAG/Rij females compared to males, a more pronounced dopamine insufficiency and alterations in serotonin metabolism were found. The results indicate that sex differences in neurochemical alterations in brain structures may underlie sex differences in the manifestation of depressive pathology in the WAG/Rij rat preclinical model.