Potential effect of spermidine on GABA, dopamine, acetylcholinesterase, oxidative stress and proinflammatory cytokines to diminish ketamine-induced psychotic symptoms in rats

Ketamine, N-methyl-d-aspartate receptor antagonist has been implanted in such behavioural and biochemical alterations in animals similar to human psychosis. Spermidine, a biogenic polyamine, involved in various cellular functions in living organisms, on the contrary possess NMDA receptor agonistic effect. Therefore, we aimed to study the effect of spermidine (10 and 20 mg/kg, i.p.) in ketamine (50 mg/kg, i.p.) induced psychotic symptoms using various behavioural animal models. Biochemical assays were done to confirm the molecular pathways associated with spermidine and psychosis. Spermidine was significant to alleviate the ketamine-induced psychotic symptoms as indicated by decrease in locomotor activity in actophotometer, stereotypic behaviours, immobility duration in force swim test and latency to climb the pole in pole climb avoidance test. Interestingly, spermidine significantly decreased acetylcholinesterase (AChE) activity, serum tumor necrosis factor (TNF-α), dopamine and malondialdehyde (MDA) level while increased gamma-amino butyric acid and reduced glutathione (GSH) level in different regions of brain. Spermidine did not produce cataleptic effect on bar test at lower dose, but at the higher dose its cataleptic effect was similar to haloperidol. Based on behavioural and biochemical results, present study revealed spermidine as a promising antipsychotic biomolecule, however, its cataleptic effect at higher doses must be ruled out before use in clinical settings.