Sex and individual differences in ketamine's effects on alcohol drinking in rats.

BACKGROUND

Effective pharmacotherapies for Alcohol Use Disorder (AUD) are lacking, and factors such as sex, drinking patterns, and timing of treatment during the addiction cycle may influence treatment efficacy. Clinical studies suggest that ketamine may be effective in AUD; however, preclinical findings have been inconclusive, likely due to varying rodent strains, intake protocols, and ketamine doses/routes. This study investigated ketamine's effects on alcohol drinking in male and female Long Evans rats using multiple validated paradigms.

METHODS

In Experiments 1 and 2, rats underwent 4 weeks of intermittent access two-bottle choice (IA2BC) drinking. In Week 5, they received ketamine via intravenous infusion (0.0, 1.47, or 2.35 mg/kg) or intraperitoneal injection (0.0, 10, or 20 mg/kg) during acute withdrawal. Alcohol intake was monitored 24 h posttreatment and for 3 weeks to assess sustained effects. In Experiment 3, rats completed a modified drinking-in-the-dark (DID) protocol for 2 weeks, followed by 2 weeks of forced abstinence. A single ketamine injection preceded re-exposure to alcohol. In Experiment 4, rats were categorized as high or low drinkers after five DID/abstinence cycles. During Cycle 6, six ketamine injections were administered. A final cycle assessed sustained effects.

RESULTS

In Experiments 1-3, ketamine had no significant acute or lasting effects on alcohol intake in either sex when given during acute withdrawal or following a single period of forced abstinence. In Experiment 4, moderate drinkers (low drinking females, high drinking males) showed reduced intake after the first postabstinence ketamine dose, but not to subsequent dosing. High drinking females responded to both initial and repeated treatments; however, effects did not persist after treatment cessation.

CONCLUSIONS

Ketamine's ability to reduce alcohol intake appears sex-dependent, acute rather than sustained, and limited to high-drinking females. These findings highlight the need to assess the safety of repeated or chronic ketamine use in AUD treatment.