EFFECTS OF SODIUM BENZOATE ON BEHAVIORAL AND SYNAPTIC DEFICITS INDUCED BY SUBCHRONIC KETAMINE EXPOSURE IN MICE

Abstract Background Ketamine, an N-methyl-D-aspartate receptor (NMDAR) blocker, has been used as a dissociative anesthetic and currently become a popular recreational abused substance. Repeated and chronic use of ketamine leads to behavioral disturbances, including social deficits and cognitive impairments in memory. Previous studies indicate that enhancement of NMDAR function reveals the beneficial effects on ketamine-induced abnormal behavioral and neurochemical responses. Sodium benzoate (SB), a D-amino acid oxidase inhibitor, has been reported to improve several neurological disorders, such as depression and schizophrenia, which may be associated with increasing NMDAR function. Aims & Objectives This study aimed to investigate the therapeutic effects of SB on ketamine- induced psychotomimetic behaviors and neuronal activity. Method The male ICR mice received intraperitoneal injection (i.p.) of either ketamine (20 mg/kg) or vehicle twice per day successively during postnatal days (PN) 32-46. Subsequently, SB (30 &100 mg/kg, i.p.) was given during PN55-69. The novel location/object recognition task, reciprocal social interaction, three-chamber social test, tail suspension test and forced swimming test were monitored. Moreover, a serotonergic hallucinogen was administered to induce head-twitch responses. After animal behavioral tests, the hippocampal synaptic function was determined. Results The data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including social deficits, recognition memory impairments, and increased depression- like and hallucinogen-induced head-twitch responses, were ameliorated by SB post-treatment. In addition, SB reversed the reduced hippocampal synaptic activity after repeated ketamine treatment. Discussion & Conclusion These results demonstrated that post-treatment with SB could effectively reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that SB can be used as a novel adjunct therapy with ketamine for treatment- resistant depression and provide benefits for ketamine use disorders.