Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study
Raquel Pascual-Antón, Arantxa Blasco‐Serra, Emma Muñoz‐Moreno, Fuencisla Pilar-Cuéllar, Emilio Garro-Martínez, Eva Florensa-Zanuy, Xavier López-Gil, Víctor M. Campa, Guadalupe Soria, Albert Adell
Brain Structure and Function August 7, 2021 DOI: 10.1007/s00429-021-02354-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats |
| Interventions | Ketamine Ro 25-6981 |
| Measures | diffusion-weighted magnetic resonance imaging (DWI), fractional anisotropy, immunohistochemical analyses of myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) |
| Topics | Esketamine Ketamine |
| Citations | 6 |
| Key findings | Ketamine and the GluN2B-selective antagonist Ro 25-6981 generally produced opposite structural brain changes, but both increased fractional anisotropy in the infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increased NF200 in deep infralimbic cortex and dorsal raphe nucleus, and increased MBP in infralimbic cortex. The authors suggest these protein changes may reflect new dendritic spines and myelination, and that the fractional anisotropy increases could be a biomarker of rapid antidepressant response. |
Abstract
Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague-Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.
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 4
- Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential. Aging and disease April 29, 2024
- Neuroplastic white matter changes in patients with major depression following lysergic acid diethylamide treatment Cell Reports Medicine May 7, 2026
- Potential molecular pathways and therapeutic implications of rapid-acting antidepressants on myelin biology: a scoping review. Frontiers in Neuroscience 2025
- (R)-ketamine as prophylactic and therapeutic drug for neurological disorders: beyond depression. Neuroscience & Biobehavioral Reviews June 1, 2022
Cites 22
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- 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
- A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry April 8, 2016
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 17 more in the library