Ketamine blocks bursting in the lateral habenula to rapidly relieve depression
This animal study (n=500) investigated the neural circuitry underlying the antidepressant efficacy of ketamine (10 -; 25mg/kg) in rodents and found that it blocks the activity of the lateral habenula, a network that normally inhibits reward processing, whose inhibition is in turn unblocked via ketamine.
Abstract
Introduction
The N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive.Methods/Results: Here we show that blockade of NMDAR-dependent bursting activity in the ‘anti-reward center’, the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects.
Discussion
Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.
Research Summary of 'Ketamine blocks bursting in the lateral habenula to rapidly relieve depression'
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typeindividual
- Journal
- Compound
- Topic
- APA Citation
Yang, Y., Cui, Y., Sang, K., Dong, Y., Ni, Z., Ma, S., & Hu, H. (2018). Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature, 554(7692), 317-322. https://doi.org/10.1038/nature25509
References (2)
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Zanos, P., Moaddel, P. J., Morris, P. J. et al. · Nature (2016)
Cited By (14)
Papers in Blossom that reference this study
Alexander, L., Jelen, L. A., Mehta, M. A. et al. · Neuroscience and Biobehavioral Reviews (2021)
Asim, M., Wang, B., Hao, B. et al. · Neurochemistry International (2021)
Savalia, N., Shao, L-X,, Kwan, A. C. · Trends in Neuroscience (2021)
Grieco, S. F., Qiao, X., Johnston, K. G. et al. · Translational Psychiatry (2021)
Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)
Hibicke, M., Gobbi, G. · Journal of Neuroscience (2020)
Kohtala, S., Alitalo, O., Rosenholm, M. et al. · Pharmacology and Therapeutics (2020)
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Greb, A. C., Vargas, M. V., Duim, W. C. et al. · ACS Pharmacology and Translational Science (2020)
Hashimoto, K. · Psychiatry and Clinical Neurosciences (2019)
Show all 14 papersShow fewer
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Zanos, P., Gould, T. D. · Molecular Psychiatry (2018)
Zanos, P., Thompson, S. M., Duman, R. S. et al. · CNS Drugs (2018)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.