Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP.
Paul A Parcon, Amanda Bardhoshi, Amanda Olsen-Dufour, Raven Cureton, Susovan Jana, Cheryl L. Morse, Ioline D. Henter, Julia Totis, Adrian E Jenson, Matilah T Pamie-George, Jeih-San Liow, Sami S Zoghbi, Shawn Wu, Victor W Pike, Robert B Innis
Translational Psychiatry April 21, 2026 DOI: 10.1038/s41398-026-04039-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats and rhesus macaques |
| Intervention | Ketamine |
| Dose | 10 mg/kg in rats, 0.5 mg/kg in rhesus macaques |
| Duration | Within one hour of infusion |
| Topics | Esketamine Ketamine |
| Key findings | Ketamine infusion rapidly increases cAMP activity, as indicated by increased binding of radioligands to PDE4 in rats and rhesus macaques, suggesting a mechanism for its rapid antidepressant effects. |
Abstract
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a robust, rapid-acting antidepressant whose molecular effects have not been fully elucidated. Phosphodiesterase-4 (PDE4), which terminates cyclic adenosine monophosphate (cAMP) activity, may underlie antidepressant response. In particular, previous studies found that whole brain binding of the positron emission tomography (PET) radioligand [11C](R)-rolipram to PDE4 was decreased in individuals with major depressive disorder; eight weeks of antidepressant treatment rescued this decrease in [11C](R)-rolipram binding. This study used [11C](R)-rolipram, which targets all PDE4 subtypes, and [18F]PF-06445974, which is preferential for PDE4B over PDE4D, to determine whether ketamine infusion could rapidly increase cAMP activity in rats (at 10 mg/kg) and rhesus macaques (at 0.5 mg/kg). Ketamine increased [11C](R)-rolipram binding to PDE4 in rats (mean standardized uptake value (SUV) increase=24% ± 14%, range=3%-42%, p = 0.004) and in monkeys (mean distribution volume (VT) increase=14% ± 2%, range=12%-16%, p = 0.003). Ketamine also increased [18F]PF-06445974 binding in monkeys within one hour of infusion (mean VT increase 28% ± 7%, range=16%-37%, p = 0.008). When [11C](S)-rolipram, which has no specific binding to PDE4, was used to control for the effects of ketamine on blood flow and radioligand delivery in rats, no consistent effects were observed for ketamine. Collectively, the results suggest that ketamine infusion rapidly increases cAMP activity and may be an underlying mechanism for ketamine's rapid antidepressant effects. These data support a common pathway for cAMP and antidepressant action and suggest that PDE4 inhibition, particularly PDE4B, may be an effective and rapid-acting antidepressant mechanism.
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
Cites 8
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Ketamine for the treatment of major depression: a systematic review and meta-analysis EClinicalMedicine August 1, 2023
- EFFICACY AND SAFETY OF RACEMIC KETAMINE AND ESKETAMINE FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS Expert Opinion on Drug Safety March 9, 2022
- Structural neural plasticity evoked by rapid-acting antidepressant interventions. Nature Reviews Neuroscience February 1, 2025
and 3 more in the library