Ketamine is an NMDA receptor antagonist with rapid antidepressant properties when administered at a subanesthetic dose. Preclinical models indicate that a direct injection of ketamine into the lateral habenula (Hb), a small midbrain structure with an evolutionarily preserved role in aversive learning across mammals, can rapidly relieve depression-like behavior. However, there is limited evidence to explain how ketamine acts on the function of the human Hb. In a translational computational neuroscience study, 70 healthy adult volunteers were randomized in a 1:1 ratio to receive ketamine (0.5 mg/kg) or placebo (NaCl 0.9%). We used an aversive Pavlovian conditioning paradigm combined with 7-tesla functional neuroimaging to show that ketamine attenuates Hb response during aversive stimuli expectations and outcomes 24 h post-infusion. Furthermore, we present preliminary evidence suggesting that when aversive learning occurs after ketamine infusion, reduced Hb activity during the learning process may lead to downstream effects that diminish the aversive impact of negative affective memories. These findings provide translational support for ketamine's modulation of aversive learning and Hb activity and help to refine mechanistic models of its rapid antidepressant effect.
