IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine
Satoshi Deyama, M. Kondo, Shoichi Shimada, Katsuyuki Kaneda
Translational Psychiatry May 17, 2022 DOI: 10.1038/s41398-022-01943-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Interventions | Ketamine IGF-1 neutralizing antibody BDNF IGF-1 |
| Dose | 10 and 30 mg/kg (ketamine), 160 ng/side (IGF-1 nAb), 100 ng/side (BDNF), 50 ng/side (IGF-1), 200 ng/side (BDNF nAb) |
| Duration | 5 hours (microdialysis); behavioral tests conducted 1, 3, and 4 days post-ketamine |
| Topics | Esketamine Ketamine |
| Key findings | Persistent release of IGF-1 in the medial prefrontal cortex, independently of BDNF, is essential for the antidepressant-like effects of ketamine. |
Abstract
Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.
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 17
- The role of neurotrophic factors in novel, rapid psychiatric treatments. Neuropsychopharmacology 2024
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- Ketamine and its enantiomers for depression: a bibliometric analysis from 2000 to 2023. European Archives of Psychiatry and Clinical Neuroscience April 25, 2024
- Repurposing Ketamine in the Therapy of Depression and Depression-Related Disorders: Recent Advances and Future Potential. Aging and disease April 29, 2024
- Changing your mind: neuroplastic mechanisms underlying the therapeutic effect of psychedelics in depression, PTSD, and addiction Progress in Neuro-Psychopharmacology and Biological Psychiatry October 1, 2025
and 12 more in the library
Cites 10
- 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
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacology, Biochemistry, and Behavior December 9, 2019
and 5 more in the library