Prophylactic efficacy of ketamine, but not the low-trapping NMDA receptor antagonist AZD6765, against stress-induced maladaptive behavior and 4E-BP1-related synaptic protein synthesis impairment.
A. Camargo, A. C. N. Torrá, A. P. Dalmagro, Ana Paula Valverde, Bruna R. Kouba, D. B. Fraga, Eloise C Alves, A. L. S. Rodrigues
Progress in Neuro-Psychopharmacology and Biological Psychiatry 2022 DOI: 10.1016/j.pnpbp.2022.110509 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice subjected to chronic restraint stress |
| Interventions | Ketamine AZD6765 |
| Dose | ketamine 5 mg/kg, i.p.; ketamine 1 mg/kg, i.p.; AZD6765 1 or 5 mg/kg, i.p. |
| Duration | Single administration 1 week before a 10-day chronic restraint stress protocol (2 h/day) |
| Measures | tail suspension test, splash test, self-grooming assessment, 4E-BP1 phosphorylation, PSD-95 immunocontent, GluA1 immunocontent |
| Topics | Esketamine Ketamine |
| Key points | A single ketamine dose (5 mg/kg) given one week before chronic restraint stress prevented depressive-like behavior in mice, and ketamine at 1 and 5 mg/kg prevented anxiety-related self-grooming alterations. AZD6765 at 1 or 5 mg/kg did not prevent these behaviors. Ketamine at 5 mg/kg also prevented stress-induced reductions in 4E-BP1 phosphorylation and PSD-95 and GluA1 immunocontent in the prefrontal cortex, whereas AZD6765 did not. |
Abstract
Ketamine enhances the resilience against stress-induced depressive-like behavior, but its prophylactic efficacy in anxiety-related behaviors remains to be elucidated. Moreover, there is a need for developing novel preventive strategies against depressive- and anxiety-like behavior. AZD6765, a low-trapping NMDA receptor antagonist, shares with ketamine common molecular targets and produces rapid-onset antidepressant effects, suggesting that it could be a prophylactic agent. Therefore, this study investigated the prophylactic effect of ketamine against the depressive- and anxiety-like behavior induced by chronic restraint stress (2 h/day, for 10 days) in mice. We also investigated if AZD6765 exerts a resilience-enhancing response against these maladaptive behaviors. The contribution of 4E-BP1-related synaptic proteins synthesis (PSD-95/GluA1) in the possible pro-resilience efficacy of ketamine and AZD6765 was investigated. A single administration of ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), given 1 week before the stress protocol, was effective in preventing stress-induced depressive-like behavior in the tail suspension test and splash test. Ketamine administered at 1 and 5 mg/kg (i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.), prevented stress-induced anxiety-related self-grooming alterations. Stress-induced reduction on 4E-BP1 phosphorylation and PSD-95 and GluA1 immunocontent in the prefrontal cortex was prevented by ketamine (5 mg/kg, i.p.), but not AZD6765 (1 or 5 mg/kg, i.p.). The results indicate that ketamine, but not AZD6765, exerts a pro-resilience response against stress-induced maladaptive behavior, reinforcing that it could be a prophylactic agent to manage individuals at-risk to develop MDD and anxiety.
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
- Inflammation, stress and depression: an exploration of ketamine’s therapeutic profile Drug Discovery Today February 1, 2023
- Changes in synaptic markers after administration of ketamine or psychedelics: a systematic scoping review Frontiers in Psychiatry June 26, 2023
- Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior. Molecular Psychiatry June 1, 2025
- Prophylactic Ketamine: Current Knowledge and Future Directions. Biological Psychiatry March 28, 2025
- Novel and emerging anesthetic drugs for the treatments of major depression: a comprehensive review of efficacy, mechanism, and outlook. Frontiers in Psychiatry 2025
Cites 15
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- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects Molecular Psychiatry October 15, 2013
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and 10 more in the library