Abstract

Drug withdrawal is recognized as a global health issue. Abuse of dextromethorphan (DXM), an over-the-counter antitussive, leads to addiction and withdrawal symptoms by acting on glutamate N-methyl-D-aspartate (NMDA) receptors. Nonetheless, effective agents for alleviating withdrawal symptoms remain limited, underlining the crucial need for novel treatments which ideally would include natural, acceptable and accessible preparations derived from functional foods. This study aimed to explore the effects of treatment with pre-germinated brown rice (PGBR), considered a functional food due to its bioactive components, on behaviors and hippocampal NMDA glutamate receptor subunit 1 (NMDAR1) protein in a rat model of drug withdrawal from DXM administration. Locomotor activity, anxiety-like behavior, and NMDAR-1 protein levels in the hippocampus were assessed after PGBR treatment in DXM-induced withdrawal rats compared with diazepam, a drug commonly used to treat withdrawal symptoms, and gamma-aminobutyric acid (GABA), a compound enriched in PGBR for 30 and 60 days. PGBR treatment, starting from 30 days, effectively prevented the increase in locomotor activity, anxiogenic-like behavior, and the decrease of NMDAR1 protein in the hippocampus during DXM-induced withdrawal. GABA treatment partially restored locomotor activity and NMDAR1 protein levels at 60 days. Diazepam showed only partial recovery in the anxiety test after 30 days, whereas anxiety-like behavior re-emerged following 60 days of treatment. Our results indicate that PGBR impacts drug withdrawal symptoms and influences glutamate neurotransmission through modulation of glutamate NMDAR1 receptor, possibly due to the complex actions of various bioactive compounds. Furthermore, long-term PGBR treatment showed no adverse effect on behavior and NMDAR1 protein. These findings suggest that PGBR may serve as a natural agent to mitigate behavioral and molecular alterations associated with drug withdrawal in rodent models, thereby endorsing its potential for further translational research beyond the current preclinical phase.