Ketamine attenuates habenula activity in response to aversive outcomes during Pavlovian learning
Erdem Pulcu, Sara Costi, Pilar Artiach-Hortelano, Chloe Wigg, Sorcha Hamilton, Marieke Martens, Rebecca Lawson, Rupert McShane, Philip J. Cowen, Susannah E Murphy, Catherine J Harmer
bioRxiv (Cold Spring Harbor Laboratory) February 10, 2026 preprint DOI: 10.64898/2026.02.08.704729 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial |
|---|---|
| Sample size | 70 |
| Population | Healthy adult volunteers |
| Intervention | Ketamine |
| Dose | sub-anesthetic dose |
| Topics | Ketamine Esketamine |
| Keywords | Habenula Midbrain Aversive stimulus Nmda receptor Antagonist Escape response Classical conditioning Amygdala Neurochemical Associative learning |
| Key findings | Ketamine attenuates human habenula response during aversive stimuli expectations and outcomes 24 hours post-infusion. |
Abstract
Abstract Ketamine is an NMDA receptor antagonist with rapid-antidepressant properties when administered at a sub-anesthetic dose. Preclinical models indicate that a direct injection of ketamine into 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 habenula. In a translational computational neuroscience study, 70 healthy adult volunteers were randomised in a 1:1 ratio to receive ketamine or placebo (NaCl 0.9%). We used an aversive Pavlovian conditioning paradigm combined with 7-Tesla functional neuroimaging to show that ketamine attenuates habenula response during aversive stimuli expectations and outcomes 24 hours post-infusion. We further present preliminary evidence suggesting that when aversive learning occurs after ketamine infusion, reduced habenula 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 preclinical models of ketamine’s mechanisms in humans.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |
Citations in the library
Cites 6
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- The use of ketamine as an antidepressant: a systematic review and meta‐analysis Human Psychopharmacology: Clinical and Experimental April 7, 2015
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Distinct Neuropsychological Mechanisms May Explain Delayed- Versus Rapid-Onset Antidepressant Efficacy Neuropsychopharmacology March 5, 2015
- Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models. Neuropharmacology November 1, 2024
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