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Background <p>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.&#xa0;</p> Methods <p>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.</p> Results <p>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&#xa0;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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Elisabetta Ciccocioppo,
  • Sara Massetti,
  • Marcus W. Meinhardt,
  • Fabio Fumagalli,
  • Patrizia Romualdi,
  • Marisa Roberto,
  • Rainer Spanagel,
  • Roberto Ciccocioppo,
  • Esi Domi

摘要

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.