Mechanisms underlying sustained resilience against anorexia nervosa from sub-anesthetic ketamine: A review and new research based on electron microscopic analyses of synapses using a mouse model.
Yiru Dong, Sebastian Goodwin-Groen, Jessie Ma, Esther Kim, Sophia Del Giudice, Michael Santos, Chiye Aoki
Physiology & Behavior September 1, 2025 DOI: 10.1016/j.physbeh.2025.114956 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Rodents (activity-based anorexia model) |
| Intervention | Ketamine |
| Dose | sub-anesthetic |
| Topics | Esketamine Ketamine |
| Keywords | Activity-based anorexia Drebrin Glun2b Inhibitory synapses Medial prefrontal cortex Ketamine therapy Neuroscience hippocampus Neural connections |
| Citations | 4 |
| Key findings | Sub-anesthetic ketamine administered during ABA in mid-adolescence promotes resilience against ABA relapses by increasing GluN2B-containing NMDA receptors and drebrin at mPFC excitatory synapses and augmenting GABAergic inhibition in the hippocampus, which suppresses starvation-evoked hyperactivity and improves weight gain. |
Abstract
The activity-based anorexia (ABA) animal model captures key maladaptive behaviors of anorexia nervosa - starvation-evoked hyperactivity, voluntary food restriction, severe weight loss and elevated anxiety-like behavior. By repeating ABA induction, the model reveals an animal's gain of resilience against ABA relapses and concomitant synaptic plasticity. We review findings on the efficacy of sub-anesthetic ketamine administered during ABA in mid-adolescence in gaining resilience against ABA relapses, and the molecular changes evoked at medial prefrontal cortex (mPFC) synapses. GluN2B-containing NMDA receptors are significantly greater at excitatory synapses on dendritic spines of pyramidal cells. Drebrin, an F-actin binding protein that promotes activity-dependent trafficking of NMDA receptors to synaptic membranes, also increases at excitatory synapses on GABA-interneurons and pyramidal cells. These changes are at sites very near (15 days post-injection, during ABA relapse in late adolescence. Ketamine treatment during ABA in late-adolescence ameliorates ABA relapse in adulthood >15 days later but to a lesser extent. A new EM analysis revealed that wheel running promotes GABAergic inhibitory synapse formation on pyramidal cells of the hippocampus and that ketamine augments GABAergic inhibition's contribution towards suppression of the most maladaptive behavior - starvation-evoked hyperactivity - while also augmenting food consumption, as reflected by weight gain at the end of food availability periods.
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 2
- Psilocybin exerts differential effects on social behavior and inflammation in mice in contexts of activity-based anorexia Psychedelics February 3, 2026
- Psilocybin exerts differential effects on social behaviour and inflammation in mice in contexts of activity-based anorexia (ABA) bioRxiv (Cold Spring Harbor Laboratory) October 15, 2025
Cites 10
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions The Quarterly journal of medicine July 1, 1998
and 5 more in the library