S-ketamine, but not R-ketamine, transiently suppresses front-loaded binge-like alcohol self-administration in male rats

Background and

Purpose: Ketamine has emerged as a promising treatment candidate for alcohol use disorder (AUD), yet whether its S- and R-enantiomers differentially regulate ongoing binge-like alcohol self-administration remains unknown. We compared the acute and repeated effects of S- and R-ketamine in a chronic binge-like, front-loaded operant alcohol self-administration paradigm. Experimental Approach: Male Long–Evans rats were trained to self-administer alcohol chronically during short operant sessions. We assessed the dose-response effects of both S- and R-ketamine on alcohol intake, operant responding, within-session drinking microstructure, tolerance across repeated administrations, and functional cross-tolerance between enantiomers. Control measures included locomotor activity, inactive lever responding, magazine-directed behaviour and multiple task-initiation measures. Key

Results: S-ketamine dose-dependently suppressed alcohol self-administration, with maximal efficacy at 40 mg/kg. This effect remained robust both 2 h and 4 h after administration, selectively attenuated front-loaded alcohol responding and occurred without detectable alterations in locomotor activity, inactive responding, magazine-directed behaviour or task initiation, arguing against a nonspecific sedative or motor-impairing effect. However, efficacy rapidly declined after repeated administration indicating rapid tolerance across repeated administrations. In contrast, R-ketamine failed to modify alcohol intake or drinking microstructure under identical conditions, including at 2 h and 4 h post-injection and repeated R-ketamine exposure did not attenuate subsequent S-ketamine efficacy. Conclusion and

Implications: These findings identify S-ketamine as the behaviourally active ketamine enantiomer in this chronic binge-like alcohol self-administration model and highlight stereochemistry, dosing schedule, and alcohol exposure pattern as key determinants of ketamine efficacy in AUD.