DIFFERENTIAL EFFECTS OF S- AND R-KETAMINE ON RETROSPLENIAL CORTEX PLASTICITY AND DISSOCIATIVE-LIKE BEHAVIORS IN MALE WISTAR RATS

Ketamine produces rapid antidepressant effects but is also associated with dissociative side effects that may limit its long-term clinical use. The retrosplenial cortex (RSC) has emerged as a key brain region implicated in ketamine-induced dissociative states. However, the effect of repeated treatment with ketamine enantiomers on RSC has not been systematically examined. In this study, we investigated the effects of acute (first dose) and repeated (seventh dose) administration of ketamine enantiomers on molecular markers of neural plasticity (c-Fos, ΔFosB) and dissociation-like behavior (ataxia) in adult male Wistar rats (12 weeks of age). Animals received repeated subcutaneous injections of saline, S-ketamine (15, 30 mg/kg), or R-ketamine (15, 30 mg/kg). Acute administration of S-ketamine resulted in increased c-Fos expression in the RSC, whereas repeated treatment led to ΔFosB accumulation accompanied by the absence of c-Fos induction. R-ketamine did not induce molecular changes in the RSC. Behaviorally, ataxia was observed only following S-ketamine administration. Repeated S-ketamine treatment led to the development of tolerance to ataxia. These findings demonstrate that S-ketamine, but not R-ketamine, affects RSC and produces dissociative-like behavioral effects. The accumulation of ΔFosB in the RSC following repeated S-ketamine exposure, together with reduced c-Fos induction, suggests persistent neuroplastic adaptations that may underlie the development of tolerance to dissociative effects. Further studies are needed to evaluate the relevance of these findings for clinical S-ketamine treatment (e.g., esketamine/Spravato), including both its adverse dissociative effects and therapeutic outcomes.