Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP.

Overview

Authors: Paul A Parcon¹, Amanda Bardhoshi¹, Amanda Olsen-Dufour¹, Raven Cureton¹, Susovan Jana¹, Cheryl L Morse¹, Ioline D Henter¹, Julia Totis¹, Adrian E Jenson¹, Matilah T Pamie-George¹, Jeih-San Liow¹, Sami S Zoghbi¹, Shawn Wu¹, Victor W Pike¹, Robert B Innis¹

ORCID iDs: Paul A Parcon, Susovan Jana, Julia Totis, Matilah T Pamie-George, Victor W Pike

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD USA

Institutions: National Institutes of Health (United States); National Institute of Mental Health (United States)

Journal: Translational psychiatry, volume 16, issue 1, article 297

Dates: received 26 September 2025; accepted 9 April 2026; published online 21 April 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41398-026-04039-w · PMID 42014381 · PMCID PMC13233975 · OpenAlex W7155037433

Open access: gold, a free copy (OpenAlex)

Status: data only

Categories: PET / SPECT (modality), rat (organism), non-human primate (organism), depression (population), clinical / translational (subfield)

Methods: Statistics

Keywords: Biomarkers, Neuroscience, Depression

MeSH: Antidepressive Agents*, Brain*, Cyclic AMP*, Cyclic Nucleotide Phosphodiesterases, Type 4*, Ketamine*, Animals, Carbon Radioisotopes, Macaca mulatta, Male, Phosphodiesterase 4 Inhibitors, Positron-Emission Tomography, Pyrazoles, Pyridazines, Rats, Rats, Sprague-Dawley, Rolipram (* major topic)

Topic: Phosphodiesterase function and regulation (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex

Funding: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) (ZIAMH002793, ZIAMH002852)

Citations: not cited yet (Europe PMC); 31 references in the paper

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

openneuro:ds007653, at OpenNeuro; found in “Data availability”

Data availability

The data that support the findings of this study are available on OpenNeuro (https://openneuro.org/datasets/ds007653).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 3 keywords, 16 MeSH terms, 1 funder, 30 references.

Cite

This paper

Parcon, P. A., Bardhoshi, A., Olsen-Dufour, A., Cureton, R., Jana, S., Morse, C. L., Henter, I. D., Totis, J., Jenson, A. E., Pamie-George, M. T., Liow, J.-S., Zoghbi, S. S., Wu, S., Pike, V. W., & Innis, R. B. (2026). Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP. Translational psychiatry, 16(1), 297. https://doi.org/10.1038/s41398-026-04039-w

BibTeX

@article{parcon2026subanesthetic, author = {Parcon, Paul A and Bardhoshi, Amanda and Olsen-Dufour, Amanda and Cureton, Raven and Jana, Susovan and Morse, Cheryl L and Henter, Ioline D and Totis, Julia and Jenson, Adrian E and Pamie-George, Matilah T and Liow, Jeih-San and Zoghbi, Sami S and Wu, Shawn and Pike, Victor W and Innis, Robert B}, title = {{Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP}}, journal = {Translational psychiatry}, year = {2026}, month = apr, volume = {16}, number = {1}, pages = {297}, publisher = {Nature Publishing Group}, issn = {2158-3188}, doi = {10.1038/s41398-026-04039-w}, url = {https://doi.org/10.1038/s41398-026-04039-w}, pmid = {42014381}, pmcid = {PMC13233975} }

RIS

TY - JOUR AU - Parcon, Paul A AU - Bardhoshi, Amanda AU - Olsen-Dufour, Amanda AU - Cureton, Raven AU - Jana, Susovan AU - Morse, Cheryl L AU - Henter, Ioline D AU - Totis, Julia AU - Jenson, Adrian E AU - Pamie-George, Matilah T AU - Liow, Jeih-San AU - Zoghbi, Sami S AU - Wu, Shawn AU - Pike, Victor W AU - Innis, Robert B TI - Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP T2 - Translational psychiatry J2 - Transl Psychiatry PY - 2026 DA - 2026/04/21 VL - 16 IS - 1 SP - 297 SN - 2158-3188 PB - Nature Publishing Group DO - 10.1038/s41398-026-04039-w UR - https://doi.org/10.1038/s41398-026-04039-w LA - en ER -

CSL-JSON

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