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.
Activating the kappa opioid receptor system with the agonist salvinorin A caused dose-dependent decreases in self-grooming behavior in male mice, indicating anhedonia. Two short-acting kappa antagonists, LY2444296 and LY2795050, dose- and time-dependently prevented these grooming deficits. At kappa-selective doses, both antagonists also reduced immobility in the forced swim test, suggesting anti-anhedonia effects. The findings implicate the kappa-receptor system in an ethologically relevant measure of anhedonia and show that these antagonists can produce effects consistent with rapid anti-anhedonia.