Abstract / Summary
Aim: Childhood stress can alter adolescent stress responses, predisposing individuals to neurochemical imbalances associated with psychosis later in life. Antipsychotic treatments are limited by extrapyramidal and metabolic side effects with insignificant impact on stress-related abnormalities in schizophrenia. Flavonoids such as apigenin may offer a safer therapeutic alternative with broader neuroprotective effects. This study evaluated the effects of apigenin on serotonin and noradrenaline (NA) systems and psychotic-like behaviours in a two-hit neurodevelopmental rat model of psychosis. Methods: Sixty-four male rats at postnatal day (PND) 21 were assigned to either group-housed or isolation-reared conditions from PND 23–85 and divided into eight groups (n = 8). From PND 28–85, animals received saline (0.9% NaCl) or ketamine (16 mg/kg, i.p.). Apigenin (8 mg/kg, i.p.) or risperidone (0.5 mg/kg, i.p.) was administered from PND 60–85. Anxiety-like behaviour and working memory were assessed using the Elevated Plus Maze (EPM) and Y-Maze on PND 82 and 83, respectively. On PND 86, animals were sacrificed, and the amygdala, hippocampus, and prefrontal cortex were analyzed for serotonin and NA levels using ELISA (enzyme-linked immunosorbent assay). Results: Apigenin increased time spent and entries into the closed arms of the EPM, indicating anxiogenic effects. Although ketamine and isolation rearing produced no significant difference in the Y-maze test compared to vehicle, apigenin improved spontaneous alternation in both housing conditions. In group-housed rats, apigenin significantly (p < 0.05) increased serotonin and NA levels in the amygdala and hippocampus, while in the prefrontal, it increased serotonin levels with no significant effect on NA levels when compared to ketamine only control. In isolation-reared rats, it produced a marked increase in serotonin levels in all the examined brain regions, including increased NA levels in the amygdala with differential reduction in NA levels in both hippocampus and pre-frontal cortex when compared with ketamine control. Conclusions: Apigenin exerted anxiogenic effects while improving working memory and enhancing monoaminergic neurotransmission, suggesting potential therapeutic benefits for negative symptoms associated with schizophrenia.