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

Ketamine reduces alcohol seeking in female but not male rats, including in a model of stress combined with cues that trigger relapse. A dose of 10 mg/kg ketamine selectively lowered alcohol self-administration and stress-plus-cue-induced reinstatement of alcohol seeking in females. The same dose reduced reinstatement of saccharin seeking in both sexes. The NMDA receptor antagonist memantine reduced alcohol seeking in both sexes, while the ketamine metabolite hydroxynorketamine had no effect. These findings suggest that NMDA receptor antagonism may broadly reduce stress-related alcohol seeking, but ketamine has unique properties producing female-specific effects on alcohol-motivated behaviors.

Study at a glance

Abstract

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. 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). 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. 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.