Sex-Specific Effects of Repeated Ketamine Exposure on Locomotor Activity in Mice: Influence of Social and Isolated Housing Conditions

Background Recent evidence indicates that ketamine, an NMDA receptor antagonist, has rapid antidepressant effects in treatment-resistant patients. However, the club drug ketamine is widely abused, raising concerns about long-term treatment safety. Ketamine is often used at 2.5–10 mg/kg to examine antidepressant effects. Therefore, the abuse potential of repeated ketamine injections at 10mg/kg needs to be investigated. There is very little understanding of why there are sex differences in risk for these conditions. Aims & Objectives The aim of this study is to investigate the abuse potential of repeated ketamine exposure by examining its effects on locomotor activity in male and female mice under different housing conditions. Method In this study, we examined the abuse potential of repeated exposure to 10 mg/kg ketamine administered once daily for six days. Acute locomotor effects and locomotor sensitization were compared in male and female mice. Directly after weaning at postnatal day 28, male and female mice were moved to a different cage and were randomly assigned to either of two housing conditions; housed individually (ISO) or housed socially (GH) with littermates. Results No differences were observed in the acute locomotor activity to ketamine or saline administration. Interestingly, the responses were considerably greater in the ISO male mice than other groups. With repeated administration ketamine, GH- female and male, and ISO female mice showed a gentle increase in locomotor activity. However, ketamine-treated ISO male mice was significantly decreased locomotor activity comparing Day1 and Day6. Discussion & Conclusions Taken together, the results demonstrate that repeated ketamine induces GH- and ISO- female mice showed a great escalation in activity, indicated behavioral sensitization. Acute ketamine-treated ISO male mice showed increased locomotor activity than others; however, repeated ketamine- and saline treated ISO male mice (Day6) showed significantly decreased locomotor activity comparing Day1. Our data underline fundamental sex differences in the sustained effects of ketamine with chronic ISO stress.