Učinki S- in R-ketamina na vedenje in plastičnost možganov v živalskem modelu na zdravljenje rezistentne depresije

Introduction: Ketamine, a fast-acting antidepressant, has shown promise in alleviating symptoms of treatment-resistant depression (TRD). It exists in two enantiomers, R- and S-ketamine, where preclinical studies have shown greater antidepressant effects with fewer side effects with R-ketamine. However, existing preclinical studies often employ short-term protocols, which limit their translational relevance. This doctoral thesis aimed to investigate the effects of repeated administration of ketamine enantiomers (R- and S-ketamine) in Wistar-Kyoto (WKY) rats, a model of TRD, and Wistar (W) control rats. Focus was placed on psychomotor, antidepressant, and neuroplastic effects under a treatment protocol resembling long-term clinical practice. Methods: Three experiments were conducted using adult male W and WKY rats treated with repeated subcutaneous injections of saline, R-ketamine, S-ketamine, or racemic ketamine. We evaluated the psychomotor and antidepressant effects of ketamine enantiomers. Molecular markers (c-Fos, ?FosB, BDNF, and MOR) were measured in the prefrontal cortex (PFC), nucleus accumbens (NAc), hippocampus (HPC), striatum (STR), retrosplenial cortex (RSC), and oculomotor nucleus (OMN). Results: S-ketamine induced stronger psychomotor effects than R-ketamine, including locomotor stimulation, ataxia, and stereotypy. WKY rats showed greater sensitivity to these effects. Repeated treatment led to locomotor sensitization and tolerance to ataxia. Increased c-Fos and ?FosB were observed in the RSC after S-ketamine. W rats showed overall higher ?FosB levels than WKY rats. No antidepressant-like effects were observed in WKY rats, and no changes were found in BDNF, MOR, or ?FosB in PFC, NAc, STR, and HPC. Conclusion: S-ketamine induced stronger psychomotor and neuroplastic effects compared to R-ketamine. WKY rats showed heightened sensitivity to these behavioral effects. The absence of antidepressant-like responses in WKY rats underscores the need for further investigation. Finally, the emergence of sensitization and tolerance with repeated administration suggests that patients' subjective experience of ketamine treatment may evolve, potentially impacting long-term efficacy and tolerability.