Publication: The anxiety effect of a generalized epilepsy rat model treated with zolpidem
Loading...
Date
2025-07
Authors
Murugan, Sutharshinnii A/P
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Generalized epilepsy, characterized by recurrent seizures originating from both cerebral hemispheres, is often associated with anxiety, significantly impacting patients' quality of life. This study investigated the anxiolytic effects of zolpidem, a GABAA receptor modulator, in a kainic acid (KA)-induced generalized epilepsy rat model. A total of 24 male Sprague-Dawley (SD) rats were assigned to six groups: Sham, KA only, KA + 1mg/kg zolpidem, KA + 3mg/kg zolpidem, 1mg/kg zolpidem only, and 3mg/kg zolpidem only. Generalized epilepsy induced through intraperitoneal (i.p.) administration of KA (7.5mg/kg to 15mg/kg, as needed). Zolpidem was administered orally at a daily dose for 14 consecutive days. Anxiety-related behaviours were assessed using the open-field test (OFT) before and after zolpidem treatment, while body weight, feed intake, and water consumption were monitored daily. Histopathological analysis of the hippocampus was performed using haematoxylin and eosin (H&E) staining to assess morphological alterations, including neuronal loss and disruption of tissue architecture, associated with anxiety-related pathology in kainic acid-induced generalized epilepsy, and to evaluate the potential neuroprotective effects of zolpidem treatment. KA injection successfully induced generalised epilepsy, with all KA-injected rats reaching a seizure severity score of 4 on the Modified Racine Scale. In the OFT, central zone entries significantly increased (p < 0.01) following intervention in the KA + 1mg/kg ZOL group, indicating a potential anxiolytic effect. The KA + 3mg/kg zolpidem group also showed a significant increase (p < 0.05), but the effect was less pronounced than at the lower dose. In contrast, the 3mg/kg zolpidem-only group exhibited reduced entries and time spent in the central zone post-intervention (both) showing p < 0.01), suggesting a potential anxiogenic effect at higher doses in non-epileptic animals. However, total distance travelled showed no significant differences across groups, indicating zolpidem’s effects were more specific to anxiety-related exploratory behaviour than general locomotion. These behavioural findings align with cage-side observations, which associated KA-induced generalized epilepsy with anxiety-like behaviour. No significant differences in body weight, feed efficiency, or water consumption were observed across groups. Histological analysis revealed characteristic neuronal damage in the hippocampus of KA-treated rats, including hypereosinophilia of the cytoplasm, pyknotic nuclei, and granule cell dispersion (GCD). Notably, the KA + 1mg/kg zolpidem group exhibited reduced neuronal damage compared to the KA only and KA + 3mg/kg zolpidem groups. Paradoxically, both zolpidem-only groups also displayed neurodegenerative changes, suggesting potential adverse effects of prolonged zolpidem exposure in the absence of epilepsy. These findings suggest that zolpidem at 1mg/kg reduces anxiety in generalized epilepsy, potentially mitigating the epilepsy-associated psychiatric comorbidity. However, a higher dose of 3mg/kg may exacerbate anxiety and neuronal damage, highlighting the importance of precise dosing to optimize therapeutic outcomes while minimizing adverse effects.