Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects
Open accessAbstract
Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in the medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1 H-[13 C]-nuclear magnetic resonance spectroscopy. Rats were acutely pretreated by intraperitoneal injection with a single dose of ketamine (1, 3, 10, 30 and 80 mg kg-1), Ro 25-6981 (1, 3 and 10 mg kg-1), scopolamine (5, 25 and 100 μg kg-1) or vehicle (controls). At fixed times after drug injection, animals received an intravenous infusion of [1,6-13 C 2]glucose for 8 min to enrich the amino-acid pools of the brain with 13 C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13 C enrichments were measured. We found a clear dose-dependent effect of ketamine and Ro 25-6981 on behavior and the percentage of 13 C enrichment of glutamate, glutamine and GABA (γ-aminobutyric acid). Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggest that the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Rodent studies have shown that ketamine and other NMDA receptor antagonists transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex.
“Rodent studies employing carbon-13 magnetic resonance spectroscopy ( 13 C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex.”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
The Results and Discussion report that carbon-13 NMR measures of glutamate–glutamine cycling increased in rat medial prefrontal cortex after ketamine and the NMDA receptor antagonist Ro 25-6981. The Discussion establishes that ketamine’s effect was transient, but explicitly says Ro 25-6981’s time course was not examined, so the source does not establish that its increase was transient. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBy 18 min after injection, both prefrontal 13C glutamate (~13%) and glutamine (~35%) enrichment increased in rodents.
“By 18 min after the injection, both prefrontal 13 C glutamate (~13%) and glutamine (~35%) enrichment increased [17].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
The Results section on time dependence reports that, following ketamine injection in rats, both mPFC glutamate-C4 and glutamine-C4 13C labeling increased during the 10–18-minute interval. Our copy does not give the claimed ~13% and ~35% increases for that interval; a separate dose-response result reports 9% and 38%, respectively. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn rodents, approximately 9 min after intraperitoneal injection, ketamine induces a rise in prefrontal 13C glutamine enrichment (~20%) with no changes in 13C glutamate (~1%).
“In particular, approximately 9 min after intraperitoneal injection in rodents, ketamine induces a rise in prefrontal 13 C glutamine enrichment (~20%) with no changes in 13 C glutamate (~1%) [17]”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
The Results (time-dependence section; page unavailable) report increased prefrontal 13C glutamine enrichment during the first 0.5–8.5 minutes after intraperitoneal ketamine in rats; 13C glutamate increased significantly only during the later 10–18-minute interval. This supports the early glutamine rise and lack of a significant early glutamate change, but our copy does not state the claimed approximate 20% and 1% values. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe changes in 13C-glutamine (13%) were more prominent than 13C-glutamate (1%), comparable to preclinical findings.
“Comparable to preclinical findings with 13 C MRS [17], the changes in 13 C-glutamine (13%) were more prominent than 13 C-glutamate (1%).”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
Preclinical 13C MRS data suggest disproportionate changes following ketamine administration.
“While these processes are highly coupled under normal conditions, preclinical 13 C MRS data suggest disproportionate changes following ketamine administration [16,17].”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
The approach parallels extant preclinical data, which facilitates the translatability of the biomarker between species.
“The approach parallels extent preclinical data [16,17], which facilitates the translatability of the biomarker between species.”
From The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects (2018) · cites this paper as [17]
Ketamine induces changes in presynaptic machinery in rats, possibly reflecting a change in the number of synaptic vesicles in the nerve terminals.
“Indeed, one study showed that ketamine induces changes in presynaptic machinery in rats, possibly reflecting a change in the number of synaptic vesicles in the nerve terminals 62 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [62]
The Results section reports transient changes in glutamate/GABA–glutamine cycling in rat mPFC after ketamine, not changes in presynaptic machinery. Searches for presynaptic machinery, synaptic vesicles, and nerve terminals found no passage addressing the proposed change in vesicle number. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIn rodents, low doses of ketamine drive increased glutamate release and glutamate cycling in PFC.
“In rodents, low doses of ketamine have been shown to drive the increased glutamate release 222 and glutamate cycling 223 in PFC.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [223]
Another preclinical study found that increased glutamate cycling in the medial prefrontal cortex by three classes of antidepressants was linked to rapid antidepressant effects.
“another preclinical study showed that enhanced stimulation of glutamate cycling in the mPFC via three different classes of antidepressants was associated with the onset of rapid antidepressant action (132).”
From The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology (2019) · cites this paper as [132]
Riluzole has been identified as a potential antidepressant treatment, with support in rodent models and small clinical studies.
“Riluzole has already been identified as a potential antidepressant treatment, with support for its antidepressant properties found in rodent models31 and small clinical studies.”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [31]
In rats, sub-anesthetic doses of ketamine result in a significant increase in extracellular glutamate levels and an increase in glutamate cycling in the prefrontal cortex.
“In rats, ketamine administration at sub-anesthetic doses results in a significant increase in extracellular glutamate levels 35 and an increase in glutamate cycling 44 in the prefrontal cortex.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
Li, N., Lee, B., Liu, R.-J., Banasr, M., Dwyer, J. M., Iwata, M., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2010) · Science · doi:10.1126/science.1190287 · Cited by 2,881 · see citing works
Self-citationNMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Autry, A. E., Adachi, M., Nosyreva, E., Na, E. S., Los, M. F., Cheng, P.-F., Kavalali, E. T., & Monteggia, L. M. (2011) · Nature · doi:10.1038/nature10130 · Cited by 1,926 · see citing works
Moghaddam, B., Adams, B., Verma, A., & Daly, D. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-08-02921.1997 · Cited by 1,793 · see citing works
Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Duman, R. S., & Aghajanian, G. K. (2012) · Science · doi:10.1126/science.1222939 · Cited by 1,651 · see citing works
Self-citationHomayoun, H., & Moghaddam, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.2213-07.2007 · Cited by 1,231 · see citing works
Maeng, S., Zarate, C. A., Du, J., Schloesser, R. J., McCammon, J., Chen, G., & Manji, H. K. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.05.028 · Cited by 1,103 · see citing works
Li, N., Liu, R.-J., Dwyer, J. M., Banasr, M., Lee, B., Son, H., Li, X.-Y., Aghajanian, G., & Duman, R. S. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.015 · Cited by 1,082 · see citing works
Self-citationLucki, I. (1997) · Behavioural Pharmacology · doi:10.1097/00008877-199711000-00010 · Cited by 803 · see citing works
Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression.
Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., Nemeroff, C. B., & The APA Council of Research Task Force on Novel Biomarkers and Treatments (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.15040465 · Cited by 598 · see citing works
Preskorn, S., Baker, B., Kolluri, S., Menniti, F. S., Krams, M., & Landen, J. W. (2008) · Journal of Clinical Psychopharmacology · doi:10.1097/jcp.0b013e31818a6cea · Cited by 522 · see citing works
Neuronal-glial glucose oxidation and glutamatergic-GABAergic function.
Hyder, F., Patel, A. B., Gjedde, A., Rothman, D. L., Behar, K. L., & Shulman, R. G. (2006) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600263 · Cited by 408 · see citing works
Self-citationMolecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 396 · see citing works
(1997) · American Journal of Psychiatry · doi:10.1176/ajp.154.6.805 · Cited by 392 · see citing works
Koike, H., Iijima, M., & Chaki, S. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.05.035 · Cited by 346 · see citing works
Rowland, L. M., Bustillo, J. R., Mullins, P. G., Jung, R. E., Lenroot, R., Landgraf, E., Barrow, R., Yeo, R., Lauriello, J., & Brooks, W. M. (2005) · American Journal of Psychiatry · doi:10.1176/appi.ajp.162.2.394 · Cited by 304 · see citing works
Voleti, B., Navarria, A., Liu, R.-J., Banasr, M., Li, N., Terwilliger, R., Sanacora, G., Eid, T., Aghajanian, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.04.025 · Cited by 264 · see citing works
Self-citationSanacora, G., Smith, M. A., Pathak, S., Su, H.-L., Boeijinga, P. H., McCarthy, D. J., & Quirk, M. C. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.130 · Cited by 236 · see citing works
Self-citationAntidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Review
Drevets, W. C., Zarate, C. A., & Furey, M. L. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.09.031 · Cited by 195 · see citing works
Domino, E. F., Zsigmond, E. K., Domino, L. E., Domino, K. E., Kothary, S. P., & Domino, S. E. (1982) · PubMed · Cited by 160 · see citing works
Domino, E. F., Zsigmond, E. K., Domino, L. E., Domino, K. E., Kothary, S. P., & Dominof, S. E. (1982) · Anesthesia & Analgesia · doi:10.1213/00000539-198202000-00004 · Cited by 145 · see citing works
Homayoun, H., Jackson, M., & Moghaddam, B. (2005) · Journal of Neurophysiology · doi:10.1152/jn.00875.2004 · Cited by 137 · see citing works
Chowdhury, G. M. I., Behar, K. L., Cho, W., Thomas, M. A., Rothman, D. L., & Sanacora, G. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.006 · Cited by 125 · see citing works
Self-citationDuncan, G. E., Moy, S. S., Knapp, D. J., Mueller, R. A., & Breese, G. R. (1998) · Brain Research · doi:10.1016/s0006-8993(97)01390-5 · Cited by 117 · see citing works
Miyamoto, S. (2000) · Neuropsychopharmacology · doi:10.1016/s0893-133x(99)00127-x · Cited by 105 · see citing works
Stone, J. M., Erlandsson, K., Arstad, E., Squassante, L., Teneggi, V., Bressan, R. A., Krystal, J. H., Ell, P. J., & Pilowsky, L. S. (2008) · Psychopharmacology · doi:10.1007/s00213-007-1047-x · Cited by 103 · see citing works
Witkin, J. M., Overshiner, C. D., Li, X., Catlow, J. T., Wishart, G. N., Schober, D. A., Heinz, B. A., Nikolayev, A., Tolstikov, V., Anderson, W. H., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.216804 · Cited by 99 · see citing works
Mapping the central effects of ketamine in the rat using pharmacological MRI
Littlewood, C. L., Jones, N., O’Neill, M. J., Mitchell, S. N., Tricklebank, M. D., & Williams, S. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0344-0 · Cited by 97 · see citing works
Chowdhury, G. M. I., Patel, A. B., Mason, G. F., Rothman, D. L., & Behar, K. L. (2007) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600490 · Cited by 87 · see citing works
Self-citationIltis, I., Koski, D. M., Eberly, L. E., Nelson, C. D., Deelchand, D. K., Valette, J., Uǧurbil, K., Lim, K. O., & Henry, P. (2009) · NMR in Biomedicine · doi:10.1002/nbm.1385 · Cited by 83 · see citing works
Delayed regional metabolic actions of phencyclidine
Gao, X.-M., Shirakawa, O., Du, F., & Tamminga, C. A. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90926-9 · Cited by 66 · see citing works
Enhancing ketamine translational pharmacology via receptor occupancy normalization
Shaffer, C. L., Osgood, S. M., Smith, D. L., Liu, J., & Trapa, P. E. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.07.008 · Cited by 55 · see citing works
Blunted brain metabolic response to ketamine in mice lacking D1A dopamine receptors
Miyamoto, S., Mailman, R. B., Lieberman, J. A., & Duncan, G. E. (2001) · Brain Research · doi:10.1016/s0006-8993(01)01991-6 · Cited by 47 · see citing works
Nishizawa, N., Nakao, S., Nagata, A., Hirose, T., Masuzawa, M., & Shingu, K. (2000) · Brain Research · doi:10.1016/s0006-8993(99)02426-9 · Cited by 39 · see citing works
Rapid antidepressant effects: moving right along
Martinowich, K., Jimenez, D. V., Zarate, C. A., & Manji, H. K. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.55 · Cited by 32 · see citing works
Nagy, D., Stoiljković, M., Menniti, F. S., & Hajós, M. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.298 · Cited by 29 · see citing works
NR2B subunit-specific NMDA antagonist Ro25-6981 inhibits the expression of conditioned fear
Haller, J., Nagy, R., Tóth, M., Gyimesi-Pelczer, K., & Mikics, É. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e328343d7b2 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanisms of ketamine action as an antidepressant
Zanos, P., & Gould, T. D. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.255 · Cited by 1,127 · see citing works
Duman, R. S., Sanacora, G., & Krystal, J. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.013 · Cited by 1,026 · see citing works
Self-citationBelleau, E. L., Treadway, M. T., & Pizzagalli, D. A. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.09.031 · Cited by 550 · see citing works
Targeting glutamate signalling in depression: progress and prospects
Murrough, J. W., Abdallah, C. G., & Mathew, S. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.16 · Cited by 482 · see citing works
Gut microbiome-wide association study of depressive symptoms
Radjabzadeh, D., Bosch, J. A., Uitterlinden, A. G., Zwinderman, A. H., Ikram, M. A., van Meurs, J. B. J., Luik, A. I., Nieuwdorp, M., Lok, A., van Duijn, C. M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34502-3 · Cited by 446 · see citing works
Levey, D. F., Stein, M. B., Wendt, F. R., Pathak, G. A., Zhou, H., Aslan, M., Quaden, R., Harrington, K. M., Nuñez, Y. Z., Overstreet, C., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00860-2 · Cited by 422 · see citing works
Self-citationFee, C., Banasr, M., & Sibille, E. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.024 · Cited by 329 · see citing works
Self-citationYan, Z., & Rein, B. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01092-3 · Cited by 300 · see citing works
“In rodents, low doses of ketamine have been shown to drive the increased glutamate release [222] and glutamate cycling [223] in PFC. Electrophysiological recordings similarly indicate that ketamine elevates the frequency of excitatory postsynaptic currents (EPSC) in mouse PFC pyramidal neurons…”
BackgroundNeuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Aleksandrova, L. R., & Phillips, A. G. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.08.003 · Cited by 276 · see citing works
The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects
Abdallah, C. G., De Feyter, H. M., Averill, L. A., Jiang, L., Averill, C. L., Chowdhury, G. M. I., Purohit, P., de Graaf, R. A., Esterlis, I., Juchem, C., et al. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0136-3 · Cited by 229 · see citing works
Self-citationAleksandrova, L. R., Phillips, A. G., & Wang, Y. T. (2017) · Journal of Psychiatry and Neuroscience · doi:10.1503/jpn.160175 · Cited by 228 · see citing works
An astroglial basis of major depressive disorder? An overview
Wang, Q., Jie, W., Liu, J., Yang, J., & Gao, T. (2017) · Glia · doi:10.1002/glia.23143 · Cited by 222 · see citing works
Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.05.010 · Cited by 219 · see citing works
Self-citationHare, B. D., Shinohara, R., Liu, R. J., Pothula, S., DiLeone, R. J., & Duman, R. S. (2019) · Nature Communications · doi:10.1038/s41467-018-08168-9 · Cited by 217 · see citing works
Self-citationGodfrey, K. E. M., Gardner, A. C., Kwon, S., Chea, W., & Muthukumaraswamy, S. D. (2018) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2018.08.015 · Cited by 207 · see citing works
The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders
Sanacora, G., Yan, Z., & Popoli, M. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00540-x · Cited by 197 · see citing works
Self-citationPham, T. H., & Gardier, A. M. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.02.017 · Cited by 186 · see citing works
Identifying fast-onset antidepressants using rodent models
Ramaker, M. J., & Dulawa, S. C. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.36 · Cited by 181 · see citing works
Convergent Mechanisms Underlying Rapid Antidepressant Action
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018) · CNS Drugs · doi:10.1007/s40263-018-0492-x · Cited by 171 · see citing works
Self-citationEsterlis, I., DellaGioia, N., Pietrzak, R. H., Matuskey, D., Nabulsi, N., Abdallah, C. G., Yang, J., Pittenger, C., Sanacora, G., Krystal, J. H., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.58 · Cited by 148 · see citing works
Self-citationKohtala, S. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00232-4 · Cited by 145 · see citing works
Pham, T. H., Defaix, C., Xu, X., Deng, S.-X., Fabresse, N., Alvarez, J.-C., Landry, D. W., Brachman, R. A., Denny, C. A., & Gardier, A. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.020 · Cited by 131 · see citing works
Ketamine: Mechanisms and Relevance to Treatment of Depression
Kim, J., Suzuki, K., Kavalali, E. T., & Monteggia, L. M. (2023) · Annual Review of Medicine · doi:10.1146/annurev-med-051322-120608 · Cited by 124 · see citing works
Sanacora, G., Johnson, M. R., Khan, A., Atkinson, S. D., Riesenberg, R. R., Schronen, J. P., Burke, M. A., Zajecka, J. M., Barra, L., Su, H.-L., et al. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.224 · Cited by 120 · see citing works
Self-citationZanos, P., Brown, K. A., Georgiou, P., Yuan, P., Zarate, C. A., Thompson, S. M., & Gould, T. D. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.1316-22.2022 · Cited by 115 · see citing works
Abdallah, C. G., Averill, C. L., Salas, R., Averill, L. A., Baldwin, P. R., Krystal, J. H., Mathew, S. J., & Mathalon, D. H. (2017) · Biological Psychiatry: Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2017.04.006 · Cited by 111 · see citing works
Lüscher, B., & Möhler, H. (2019) · F1000Research · doi:10.12688/f1000research.18758.1 · Cited by 105 · see citing works
Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects
Li, S.-X., Han, Y., Xu, L., Yuan, K., Zhang, R.-X., Sun, C.-Y., Xu, D.-F., Yuan, M., Deng, J.-H., Meng, S.-Q., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.85 · Cited by 100 · see citing works
Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaa087 · Cited by 99 · see citing works
Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., Filiou, M. D., Iannace, J., Labermaier, C., Maccarrone, G., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16183-x · Cited by 91 · see citing works
Amidfar, M., Woelfer, M., Réus, G. Z., Quevedo, J., Walter, M., & Kim, Y. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109668 · Cited by 90 · see citing works
Son, H., Baek, J. H., Go, B. S., Jung, D.-H., Sontakke, S. B., Chung, H. J., Lee, D. H., Roh, G. S., Kang, S. S., Cho, G. J., et al. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.09.040 · Cited by 88 · see citing works
Ng, L. H. L., Huang, Y., Han, L., Chang, R. C.-C., Chan, Y. S., & Lai, C. S. W. (2018) · Translational Psychiatry · doi:10.1038/s41398-018-0321-5 · Cited by 82 · see citing works
Cell-type specific modulation of NMDA receptors triggers antidepressant actions
Pothula, S., KATO, T., Liu, R.-J., Wu, M., Gerhard, D. M., Shinohara, R., Sliby, A., Chowdhury, G. M. I., Behar, K. L., Sanacora, G., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0796-3 · Cited by 81 · see citing works
Self-citationLazarevic, V., Yang, Y., Flais, I., & Svenningsson, P. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01246-3 · Cited by 76 · see citing works
Imaging the effect of ketamine on synaptic density (SV2A) in the living brain
Holmes, S. E., Finnema, S. J., Naganawa, M., DellaGioia, N., Holden, D., Fowles, K., Davis, M., Ropchan, J., Emory, P., Ye, Y., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01465-2 · Cited by 78 · see citing works
“For example, the increase in glutamate-glutamine cycling, which may reflect changes in presynaptic release machinery, is time-limited, and may even be decreased at the 24-hour timepoint [62], such that the major sustained change could be occurring post-synaptically.”
BackgroundSelf-citationKang, M. J. Y., Hawken, E., & Vazquez, G. H. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.860882 · Cited by 77 · see citing works
Murphy‐Royal, C., Gordon, G. R., & Bains, J. S. (2019) · Glia · doi:10.1002/glia.23610 · Cited by 75 · see citing works
Witkin, J. M., Martin, A. E., Golani, L. K., Xu, N. Z., & Smith, J. L. (2019) · Advances in pharmacology · doi:10.1016/bs.apha.2019.03.002 · Cited by 75 · see citing works
Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors
Yi, F., Bhattacharya, S., Thompson, C. M., Traynelis, S. F., & Hansen, K. B. (2019) · The Journal of Physiology · doi:10.1113/jp278168 · Cited by 73 · see citing works
Abdallah, C. G., Wrocklage, K. M., Averill, C. L., Akiki, T. J., Schweinsburg, B. C., Roy, A. M., Martini, B. A., Southwick, S. M., Krystal, J. H., & Scott, J. C. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.12 · Cited by 69 · see citing works
Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence
Subramanian, S., Haroutounian, S., Palanca, B. J. A., & Lenze, E. J. (2022) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2022.120152 · Cited by 68 · see citing works
Rapid Acting Antidepressants in Chronic Stress Models: Molecular and Cellular Mechanisms
Hare, B. D., Ghosal, S., & Duman, R. S. (2017) · Chronic Stress · doi:10.1177/2470547017697317 · Cited by 67 · see citing works
Self-citationAn update on NMDA antagonists in depression
Pochwat, B., Nowak, G., & Szewczyk, B. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1643237 · Cited by 64 · see citing works
Highland, J. N., Morris, P. J., Zanos, P., Lovett, J., Ghosh, S., Wang, A. Q., Zarate, C. A., Thomas, C. J., Moaddel, R., & Gould, T. D. (2019) · Journal of Psychopharmacology · doi:10.1177/0269881118812095 · Cited by 62 · see citing works
Rodent ketamine depression-related research: Finding patterns in a literature of variability
Polis, A. J., Fitzgerald, P. J., Hale, P. J., & Watson, B. O. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112153 · Cited by 62 · see citing works
Kokane, S. S., Armant, R. J., Bolaños‐Guzmán, C. A., & Perrotti, L. I. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2020.112548 · Cited by 62 · see citing works
McGirr, A., LeDue, J. M., Chan, A. W., Xie, Y., & Murphy, T. H. (2017) · Brain · doi:10.1093/brain/awx142 · Cited by 58 · see citing works
Kohtala, S., Theilmann, W., Rosenholm, M., Penna, L., Karabulut, G., Uusitalo, S., Järventausta, K., Yli‐Hankala, A., Yalçın, İ., Matsui, N., et al. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1364-6 · Cited by 58 · see citing works
Kim, J., & Monteggia, L. M. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112378 · Cited by 56 · see citing works
Neurobiology of the rapid-acting antidepressant effects of ketamine: impact and opportunities
Shinohara, R., Aghajanian, G. K., & Abdallah, C. G. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.12.006 · Cited by 54 · see citing works
Duclot, F., Pérez‐Taboada, I., Wright, K. N., & Kabbaj, M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.06.022 · Cited by 54 · see citing works
Rothman, D. L., de Graaf, R. A., Hyder, F., Mason, G. F., Behar, K. L., & De Feyter, H. M. (2019) · NMR in Biomedicine · doi:10.1002/nbm.4172 · Cited by 53 · see citing works
Self-citationUncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant
Xu, S., Yao, X., Li, B., Cui, R., Zhu, C., Wang, Y., & Yang, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.740996 · Cited by 51 · see citing works
Inhibition of a Descending Prefrontal Circuit Prevents Ketamine-Induced Stress Resilience in Females
Dolzani, S. D., Baratta, M. V., Moss, J. R., Leslie, N. L., Tilden, S. G., Sørensen, A. T., Watkins, L. R., Lin, Y., & Maier, S. F. (2018) · eNeuro · doi:10.1523/eneuro.0025-18.2018 · Cited by 51 · see citing works
Esterlis, I., Holmes, S. E., Sharma, P., Krystal, J. H., & DeLorenzo, C. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.08.025 · Cited by 50 · see citing works
Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors
Zaytseva, A., Bouckova, E., Wiles, M. J., Wustrau, M. H., Schmidt, I. G., Mendez-Vazquez, H., Khatri, L., & Kim, S. (2023) · eLife · doi:10.7554/elife.86022 · Cited by 48 · see citing works
Sakurai, H., Jain, F. A., Foster, S. L., Pedrelli, P., Mischoulon, D., D, M. F. M., & Cusin, C. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.07.089 · Cited by 46 · see citing works
Wang, Y., Zhang, N., Liu, L., Jiang, H., Hu, D., Wang, Z., Chen, N., & Zhang, Y. (2022) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.01.024 · Cited by 46 · see citing works
Rantamäki, T., & Kohtala, S. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018697 · Cited by 45 · see citing works
Zhang, B., Yang, X., Ye, L., Liu, R., Ye, B., Du, W., Shen, F., Li, Q., Guo, F., Liu, J., et al. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108382 · Cited by 45 · see citing works
Witkin, J. M., Knutson, D. E., Rodriguez, G. J., & Shi, S. X.-Y. (2018) · Current Pharmaceutical Design · doi:10.2174/1381612824666180730104707 · Cited by 44 · see citing works
Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives
Shin, C., & Kim, Y. (2020) · Psychiatry Investigation · doi:10.30773/pi.2019.0236 · Cited by 42 · see citing works
Silberbauer, L., Spurny‐Dworak, B., Handschuh, P. A., Klöbl, M., Bednařík, P., Reiter, B., Ritter, V., Trost, P., Konadu, M. E., Windpassinger, M., et al. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2020.549903 · Cited by 42 · see citing works
Antidepressant mechanisms of ketamine: Focus on GABAergic inhibition
Lüscher, B., Feng, M., & Jefferson, S. J. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.03.002 · Cited by 41 · see citing works
Jelen, L. A., Lythgoe, D. J., Stone, J. M., Young, A. H., & Mehta, M. A. (2025) · Nature Medicine · doi:10.1038/s41591-025-03800-w · Cited by 41 · see citing works
Differences between ketamine’s short-term and long-term effects on brain circuitry in depression
Gass, N., Becker, R., Reinwald, J., Cosa‐Linan, A., Sack, M., Weber‐Fahr, W., Vollmayr, B., & Sartorius, A. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0506-6 · Cited by 41 · see citing works
Yu, H., Li, M., Zhou, D., Lv, D., Liao, Q., Lou, Z., Shen, M., Wang, Z., Li, M., Xiao, X., et al. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.028 · Cited by 40 · see citing works
Mishra, P. K., Kumar, A., Behar, K. L., & Patel, A. B. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14544 · Cited by 39 · see citing works
Self-citationPodkowa, K., Podkowa, A., Sałat, K., Lenda, T., Pilc, A., & Pałucha-Poniewiera, A. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.08.031 · Cited by 38 · see citing works
Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine
Cardona-Acosta, A. M., & Bolaños‐Guzmán, C. A. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109374 · Cited by 36 · see citing works
Pałucha-Poniewiera, A. (2018) · Pharmacological Reports · doi:10.1016/j.pharep.2018.02.011 · Cited by 36 · see citing works
Scotton, E., Antqueviezc, B., Vasconcelos, M., Dalpiaz, G., Géa, L. P., Goularte, J. F., Colombo, R., & Rosa, A. R. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114963 · Cited by 36 · see citing works
van Calker, D., Serchov, T., Normann, C., & Biber, K. P. H. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.03.014 · Cited by 35 · see citing works
Fogaça, M. V., Daher, F., & Picciotto, M. R. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-02002-1 · Cited by 34 · see citing works
Crowley, N. A., Magee, S. N., Feng, M., Jefferson, S. J., Morris, C., Dao, N. C., Brockway, D. F., & Lüscher, B. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.02.003 · Cited by 34 · see citing works
Kim, J., Joo, Y., Son, Y., Kim, J., Kim, Y.-K., Kim, H.-K., Lee, S., & Ido, T. (2018) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2018.12.001 · Cited by 32 · see citing works
Mishra, P. K., Adusumilli, M., Deolal, P., Mason, G. F., Kumar, A., & Patel, A. B. (2020) · Neurochemistry International · doi:10.1016/j.neuint.2020.104750 · Cited by 31 · see citing works
Pałucha-Poniewiera, A., Podkowa, K., Lenda, T., & Pilc, A. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.06.022 · Cited by 30 · see citing works
Llamosas, N., Pérez-Caballero, L., Berrocoso, E., Bruzos-Cidón, C., Ugedo, L., & Torrecilla, M. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.07.022 · Cited by 30 · see citing works
Depression and the Glutamate/GABA-Glutamine Cycle
Mamelak, M. (2024) · Current Neuropharmacology · doi:10.2174/1570159x22666240815120244 · Cited by 29 · see citing works
Fogaça, M. V., Wu, M., Li, C., Li, X., Duman, R. S., & Picciotto, M. R. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01583-7 · Cited by 28 · see citing works
Self-citationKetamine and the Disinhibition Hypothesis: Neurotrophic Factor-Mediated Treatment of Depression
Borsellino, P., Krider, R. I., Chea, D., Grinnell, R., & Vida, T. A. (2023) · Pharmaceuticals · doi:10.3390/ph16050742 · Cited by 22 · see citing works
Rapid-acting antidepressant drugs modulate affective bias in rats
Hinchcliffe, J. K., Stuart, S. A., Wood, C. M., Bartlett, J. M., Kamenish, K., Arban, R., Thomas, C. W., Selimbeyoglu, A., Hurley, S., Hengerer, B., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi2403 · Cited by 27 · see citing works
Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders
Ali, D. N., Ali, H. M., Lopez, M. R., Kang, S., & Choi, D. (2024) · Cells · doi:10.3390/cells13040318 · Cited by 26 · see citing works
Lamanna, J., Isotti, F., Ferro, M., Spadini, S., Racchetti, G., Musazzi, L., & Malgaroli, A. (2022) · Scientific Reports · doi:10.1038/s41598-022-14694-w · Cited by 26 · see citing works
Functional mapping of brain synapses by the enriching activity-marker SynaptoZip
Ferro, M., Lamanna, J., Ripamonti, M., Racchetti, G., Arena, A., Spadini, S., Montesano, G., Cortese, R., Zimarino, V., & Malgaroli, A. (2017) · Nature Communications · doi:10.1038/s41467-017-01335-4 · Cited by 26 · see citing works
Halaris, A. E., & Cook, J. T. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-981-19-7376-5_21 · Cited by 25 · see citing works
Astroglial Mechanisms of Ketamine Action Include Reduced Mobility of Kir4.1-Carrying Vesicles
Stenovec, M., Božić, M., Pirnat, S., & Zorec, R. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02744-1 · Cited by 25 · see citing works
Grieco, S. F., Qiao, X., Johnston, K. G., Chen, L., Nelson, R. R., Lai, C., Holmes, T. C., & Xu, X. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01255-4 · Cited by 24 · see citing works
Chen, B. K., Luna, V. M., Shannon, M. E., Hunsberger, H. C., Mastrodonato, A., Stackmann, M., McGowan, J. C., Rubinstenn, G., & Denny, C. A. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.04.024 · Cited by 24 · see citing works
Zhang, J., Lin, L., Dai, X., Xiao, N., Ye, Q., & Chen, X. (2021) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2021.09.029 · Cited by 24 · see citing works
Self-citationTripathi, S. J., Chakraborty, S., Srikumar, B. N., Raju, T. R., & Rao, B. S. S. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1057-1 · Cited by 24 · see citing works
Perisynaptic astrocytes as a potential target for novel antidepressant drugs
Frizzo, M. E., & Ohno, Y. (2020) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2020.11.002 · Cited by 24 · see citing works
Averill, L. A., Jiang, L., Purohit, P., Coppoli, A., Averill, C. L., Roscoe, J., Kelmendi, B., Feyter, H. M. D., de Graaf, R. A., Gueorguieva, R. V., et al. (2022) · Chronic Stress · doi:10.1177/24705470221092734 · Cited by 22 · see citing works
Self-citationWeigand, A., Gärtner, M., Scheidegger, M., Wyss, P. O., Henning, A., Seifritz, E., Stippl, A., Herrera-Meléndez, A. L., Bajbouj, M., Aust, S., et al. (2022) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyac049 · Cited by 22 · see citing works
Yang, P.-S., Peng, H., Lin, T.-B., Hsieh, M., Lai, C., Lee, A., Wang, H.-H., & Ho, Y. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108269 · Cited by 21 · see citing works
Ketamine enhances novel object recognition memory reconsolidation via the BDNF/TrkB pathway in mice
Fan, J., Tang, Z.-H., Wang, S., Lei, S., Zhang, B., & Tian, S. (2021) · Physiology & Behavior · doi:10.1016/j.physbeh.2021.113626 · Cited by 21 · see citing works
Rapid and Sustained Restoration of Astrocytic Functions by Ketamine in Depression Model Mice
Ma, X., Yang, S., Zhang, Z., Liu, L., Shi, W., Yang, S., Li, S., Cai, X., & Zhou, Q. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2022.03.068 · Cited by 21 · see citing works
Self-citationChowdhury, G. M. I., Wang, P., Ciardi, A., Mamillapalli, R., Johnson, J., Zhu, W., Eid, T., Behar, K. L., & Chan, O. T. M. (2017) · Diabetes · doi:10.2337/db16-1589 · Cited by 21 · see citing works
Self-citation
- Authors
- Chowdhury, G. M. I., Zhang, J., Thomas, M., Banasr, M., Ma, X., Pittman, B., Bristow, L., Schaeffer, E., Duman, R. S., Rothman, D. L., Behar, K. L., & Sanacora, G.
- Affiliations
- Yale University (US)
- Centre for Addiction and Mental Health (CA)
- Bristol-Myers Squibb (United States) (US)
- Corresponding author
- Chowdhury, G M I
- Sanacora, G
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2016-04-12
- Volume
- 22
- Issue
- 1
- Pages
- 120-126
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC5345902
- OpenAlex
- W2336977282
- Cited by
- 197
- References
- 36
- Citations by year
- 2026: 4 · 2025: 20 · 2024: 16 · 2023: 15 · 2022: 22 · 2021: 23 · 2020: 22 · 2019: 24 · 2018: 26 · 2017: 19 · 2016: 5 · 2013: 1
- FWCI
- 19.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bristol-Myers Squibb
- Servier
- National Institutes of Health (1r01mh095104-01)
- National Center for PTSD, U.S. Department of Veterans Affairs
- National Institute of Mental Health (R01MH081211, R01-MH095104, R01MH105910)
- National Institute of Neurological Disorders and Stroke (P30NS052519)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- rapid-acting antidepressants, medial prefrontal cortex, ketamine, Ro 25-6981, scopolamine, glutamate, glutamine, GABA, 13C metabolic labeling, antidepressant-like behavior
- MeSH terms
- Animals, Antidepressive Agents, Brain, gamma-Aminobutyric Acid, Glutamine, Ketamine, Male, Magnetic Resonance Spectroscopy, Phenols, Piperidines, Scopolamine, Rats, Sprague-Dawley, Prefrontal Cortex, Glutamic Acid, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
