Guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine: Possible role of pro-synaptogenic signaling pathway.
A. Camargo, A. P. Dalmagro, A. Zeni, A. Rodrigues
Journal of Affective Disorders June 1, 2020 DOI: 10.1016/j.jad.2020.03.186 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine Guanosine |
| Dose | 0.1 mg/kg ketamine, 0.01 mg/kg guanosine |
| Topics | Esketamine Ketamine |
| Key points | Guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine in mice, associated with stimulation of synaptogenic pathways in the hippocampus and prefrontal cortex. |
Abstract
Background: Augmentation therapies may be effective strategies to potentiate the ketamine's actions with lower potential for knock-on effects. Thus, this study investigated the ability of combined administration of guanosine plus ketamine to elicit an antidepressant-like effect associated with mTOR pathway modulation. The ability of this combined administration to exert an antidepressant-like effect in a model of depression was also evaluated.
Methods: Mice were administered with subthreshold doses of ketamine (0.1 mg/kg, i.p.) and guanosine (0.01 mg/kg, p.o.) and submitted to the tail suspension test, and immunoblotting analyses (p-mTOR, p-p70S6K, PSD-95, GluA1, and synapsin) in the hippocampus and prefrontal cortex. The antidepressant-like effect of ketamine plus guanosine in mice subjected to administration of corticosterone (20 mg/kg, p.o., 21 days) was also evaluated.
Results: Ketamine plus guanosine treatment elicited an antidepressant-like effect, which was associated with increased mTOR (Ser2448) and p70S6K (Thr389) phosphorylation in the hippocampus, but not in the prefrontal cortex. Furthermore, increased PSD-95 and GluA1 immunocontent were observed in the prefrontal cortex, but not in the hippocampus of ketamine plus guanosine-treated mice. Reinforcing the notion that guanosine may potentiate the ketamine's behavioral response, a single administration of subthreshold doses of ketamine plus guanosine counteracted the corticosterone-induced depressive-like behavior.
Conclusions: Our results indicate that guanosine potentiates the antidepressant-like effect of subthreshold doses of ketamine, an effect likely associated with the stimulation of synaptogenic pathway in the hippocampus and prefrontal cortex, although with a different profile. The augmentation effect of ketamine by guanosine could have therapeutic relevance for patients with treatment-resistant depression.
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 5
- Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review Frontiers in Psychiatry June 26, 2023
- The Mechanisms Behind Rapid Antidepressant Effects of Ketamine: A Systematic Review With a Focus on Molecular Neuroplasticity Frontiers in Psychiatry April 25, 2022
- Guanosine boosts the fast, but not sustained, antidepressant-like and pro-synaptogenic effects of ketamine by stimulating mTORC1-driven signaling pathway. European Neuropsychopharmacology January 7, 2022
- Ketamine, but not guanosine, as a prophylactic agent against corticosterone-induced depressive-like behavior: Possible role of long-lasting pro-synaptogenic signaling pathway Experimental Neurology September 3, 2020
- Subthreshold doses of guanosine plus ketamine elicit antidepressant-like effect in a mouse model of depression induced by corticosterone: Role of GR/NF-κB/IDO-1 signaling. Neurochemistry International July 8, 2020
Cites 6
- 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
- Rapid Acting Antidepressants in Chronic Stress Models: Molecular and Cellular Mechanisms Chronic Stress February 1, 2017
- Single administration of agmatine reverses the depressive-like behavior induced by corticosterone in mice: Comparison with ketamine and fluoxetine. Pharmacology, Biochemistry, and Behavior October 2018
- Prophylactic ketamine alters nucleotide and neurotransmitter metabolism in brain and plasma following stress. Neuropsychopharmacology August 2018
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