(R)-Ketamine reduces alcohol intake and alcohol seeking induced by reconsolidation of alcohol-related memories in female Marchigian Sardinian alcohol-preferring rats

Background: Alcohol use disorder (AUD) represents a significant medical challenge, with available therapeutic approaches having limited efficacy. Emerging data suggest that psychedelic compounds could represent an alternative treatment for AUD. Among this class of molecules, ketamine, a dissociative psychedelic, shows promising properties. It reduces alcohol drinking in rodents and in humans it is used to treat depression, a condition often comorbid with AUD. Unfortunately, the marked dissociative and anesthetic effects of this molecule severely limit its therapeutic application. Ketamine is a racemic mixture of (S, R)-enantiomers, and the R-enantiomer possesses lower dissociative and anesthetic properties compared to the racemic mixture.  METHODS: Here, using male and female genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, we evaluated the potential efficacy of (R)-ketamine, in alcohol-related behaviours including home cage voluntary drinking and alcohol self-administration. We also evaluated whether R ketamine may affect the reconsolidation process of alcohol-related memories. Results: In the two-bottle free choice (free choice between 10% alcohol and water) 24-h drinking paradigm R-ketamine given orally (10, 20 and 40 mg/kg) significantly reduced alcohol consumption in female but not in male rats. No effect was observed on alcohol self-administration. We subsequently tested (R)-ketamine on alcohol memory consolidation/ retrieval task and found a significant attenuation in the retrieval of alcohol-related memories in female but not in male msP rats. Conclusions: Taken together, our findings indicate that (R)-ketamine attenuates alcohol-related behaviors in a sex-dependent manner with females showing a higher sensitivity to its effects. Given its more favorable safety profile compared to the racemic mixture, these results support the clinical investigation of (R)-ketamine as a therapeutic intervention in patients with AUD. Particular attention should be paid to sex-specific effects observed with (R)-ketamine, as they may have important clinical implications.