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. 2025 Sep;242(9):2035-2045.
doi: 10.1007/s00213-025-06782-2. Epub 2025 Apr 8.

Sex specific effects of ketamine, but not other glutamate receptor modulators, on ethanol self-administration and reinstatement of ethanol seeking in rats

Megan L Bertholomey  1   2 , Camryn Forbes  1 , Bryan D McElroy  1   3 , Mary M Torregrossa  4
Affiliations

Sex specific effects of ketamine, but not other glutamate receptor modulators, on ethanol self-administration and reinstatement of ethanol seeking in rats

Megan L Bertholomey et al. Psychopharmacology (Berl). 2025 Sep.

Abstract

Rationale: Alcohol use and major depressive disorder are frequently comorbid, with individuals diagnosed with a substance use disorder being nearly three times as likely to have major depression. Poor treatment responses are found for both disorders and are further complicated when they co-occur, underscoring the need for better therapies. One potential candidate is ketamine, which has been shown to have rapid and long-lasting effects in individuals with treatment-resistant depression and, in some studies, reduces drinking in alcohol use disorder. However, though women are more likely to have this comorbidity, few studies have examined sex-specific effects of ketamine on alcohol drinking, nor have studies assessed the potential for ketamine to reduce reinstatement of alcohol seeking.

Objectives: The primary goal of the present studies was to determine the effects of ketamine on alcohol-motivated behaviors in male and female rats, including in a model of stress + cue-induced reinstatement of alcohol seeking using yohimbine (YOH).

Results: We found a selective reduction in alcohol self-administration and YOH + cue-induced reinstatement in females, but not males at a dose of 10 mg/kg ketamine. However, the same dose of ketamine was effective in reducing YOH + cue-induced reinstatement of saccharin seeking in both sexes. In addition, a different NMDAR antagonist, memantine, was effective in reducing alcohol seeking in both sexes, while the ketamine metabolite hydroxynorketamine (HNK) had no effects.

Conclusions: In summary, these data suggest that antagonism of NMDARs may be effective in reducing stress-related alcohol seeking, but that ketamine has unique properties that lead to female-specific effects on alcohol seeking.

Keywords: 2R,6R hydroxynorketamine; AMPA receptor; Alcohol; Ketamine; Memantine; NMDA receptor; Reinstatement; Sex differences; Stress.

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Conflict of interest statement

Declarations. Ethical approval: All procedures were conducted in accordance with the policies set forth by University of Pittsburgh Institutional Animal Care and Use Committee and the National Institutes of Health Guidelines on the Care and Use of Laboratory Animals. Competing Interests: The authors declare no competing interests.

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References

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