Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens.
Federica Lucantonio, Jacob Roeglin, Shuwen Li, Jaden Lu, Aleesha Shi, Katherine Czerpaniak, Francesca R Fiocchi, Leonardo Bontempi, Brenda C. Shields, Carlos A. Zarate, Michael R. Tadross, Marco Pignatelli
Neuron May 7, 2025 DOI: 10.1016/j.neuron.2025.02.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice subjected to chronic stress |
| Intervention | Ketamine |
| Dose | a single exposure |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Neuroscience research Reward circuits Ampa receptors D1 msns Anhedonia Nucleus accumbens Prefrontal cortex Stress Sustained antidepressant response Ventral hippocampus Depression treatment Ketamine therapy |
| Citations | 24 |
| Key findings | Ketamine rescues anhedonia by restoring stress-induced weakening of excitatory synapses on nucleus accumbens D1-MSNs, with inputs from the medial prefrontal cortex and ventral hippocampus. |
Abstract
Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc-D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). Using a cell-specific pharmacology method, we establish the necessity of this synaptic restoration for the sustained therapeutic effects of ketamine on anhedonia. Examining causal sufficiency, artificially increasing excitatory synaptic strength onto D1-MSNs recapitulates the behavioral amelioration induced by ketamine. Finally, we used opto- and chemogenetic approaches to determine the presynaptic origin of the relevant synapses, implicating monosynaptic inputs from the medial prefrontal cortex and ventral hippocampus.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 9
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- Cortical Mechanisms Contributing to Ketamine-Induced Dissociation The Neuroscientist December 26, 2025
- The cognitive neuroscience of ketamine in major depression. Brain June 30, 2025
- Ketamine Improves Anhedonic Phenotypes Across Species: Translational Evidence From the Probabilistic Reward Task. Biological Psychiatry Global Open Science May 1, 2026
- The dynamics of AMPA receptors underlies the efficacy of ketamine in treatment resistant patients with depression Molecular Psychiatry March 5, 2026
and 4 more in the library
Cites 17
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
and 12 more in the library