The Effect of Valproic Acid Administration on Learning, Social Interaction, and Depression Induced by Withdrawal Syndrome in Morphine-dependent Mice.

Background: Opioids can lead to mood disorders, anxiety, depression, and cognitive impairment. Valproic acid (VPA) has neuroprotective effects that can prevent neural degeneration. This study aims to examine the impact of VPA on learning, social interaction, and depression in mice dependent on morphine.

Methods: Subjects were divided into four groups and received injections of saline, VPA, morphine, or a combination of VPA and morphine for eight days. Behavioral tests were conducted on day 8, and then administration of VPA and morphine was stopped, leading to spontaneous withdrawal syndrome. Behavioral tests were repeated on day 11, and histological analysis was performed on the hippocampus.

Findings: The preference index (PI%) decreased in the novel object recognition test in the VPA and morphine sulfate (MOR) groups compared to the control (CTL) group in the chronic phase. The concomitant administration of VPA and morphine caused an increase in social interaction criteria in both the chronic and withdrawal phases. The decrease in immobility time in the VPA and MOR+VPA groups compared to the CTL group in the withdrawal phase was not statistically significant in the tail suspension test (TST). In Nissl staining, the combination of MOR+VPA led to a significant decrease in the DC/All cell ratio compared to the individual MOR and VPA groups (P<0.05).

Conclusion: VPA may improve social relationships and depression indices during morphine withdrawal. VPA may potentially mitigate the cellular changes in the CA1 of the hippocampus induced by morphine.