A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice
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Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high - frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high - frequency correlated electroencephalogram ( EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[ f ]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned - place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants.
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Effects of negative allosteric modulators of α5GABAARs are observed both 1 hour and 24 hours following administration.
“Although it is not entirely clear how positive and negative modulation of the same receptor subtype could have antidepressant-like effects, it should be noted that the effects of the negative allosteric modulators are observed both 1 hour and 24 hours following administration.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [141]
Administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA receptors promotes coherent network activity via disinhibition of excitatory neurotransmission and exerts rapid antidepressant actions in several animal tests.
“Further supporting this hypothesis, administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABAA receptors, which are selectively expressed in the forebrain, including prefrontal cortex and hippocampus, promote coherent network activity via disinhibition of excitatory neurotransmission 45 and exert rapid antidepressant actions in several animal tests 46–”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [47]
Ketamine, similar to negative allosteric modulators of alpha5-containing GABAA receptors, enhances gamma band EEG power, which is hypothesized to be directly related to cortical disinhibition.
“Notably, ketamine 13, similar to negative allosteric modulators of alpha5-containing GABAA receptors 47, enhance gamma band electroencephalography power, which is hypothesized to be directly related to cortical disinhibition 49–52”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [47]
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Cites
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,501 · see citing works
Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., Niederehe, G., Thase, M. E., Lavori, P. W., Lebowitz, B. D., et al. (2006) · American Journal of Psychiatry · doi:10.1176/ajp.2006.163.11.1905 · Cited by 5,643 · cited 1× · see citing works
“Selective serotonin reuptake inhibitors (SSRIs), the current standard medicinal treatment for major depression, are effective in only some patients and typically require many weeks to produce their therapeutic effects (Rush et al., 2006; Gaynes et al., 2009).”
BackgroundAntidepressant effects of ketamine in depressed patients
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., & Krystal, J. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00230-9 · Cited by 3,856 · see citing works
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
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
NMDA 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
Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms
Pittenger, C., & Duman, R. S. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301574 · Cited by 1,795 · see citing works
NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., et al. (2016) · Nature · doi:10.1038/nature17998 · Cited by 1,609 · 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
Rush, A. J. (2006) · American Journal of Psychiatry · doi:10.1176/appi.ajp.163.11.1905 · Cited by 879 · see citing works
Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes
Rudolph, U., & Knoflach, F. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3502 · Cited by 733 · cited 2× · see citing works
“, 2009) and are under development as cognitive enhancers (Rudolph and Knoflach, 2011).”
BackgroundMorgan, C. J. A., Curran, H. V., & the Independent Scientific Committee on Drugs (ISCD) (2012) · Addiction · doi:10.1111/j.1360-0443.2011.03576.x · Cited by 667 · see citing works
Gaynes, B. N., Warden, D., Trivedi, M. H., Wisniewski, S. R., Fava, M., & Rush, A. J. (2009) · Psychiatric Services · doi:10.1176/ps.2009.60.11.1439 · Cited by 661 · see citing works
Yuen, E. Y., Wei, J., Liu, W., Zhong, P., Li, X., & Yan, Z. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.033 · Cited by 558 · see citing works
Singh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., De Bruecker, G., Tadic, A., Sienaert, P., Wiegand, F., Manji, H., et al. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.10.018 · Cited by 466 · see citing works
Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens
Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., & Malenka, R. C. (2012) · Nature · doi:10.1038/nature11160 · Cited by 368 · see citing works
Comparative molecular neuroanatomy of cloned GABAA receptor subunits in the rat CNS
Persohn, E., Malherbe, P., & Richards, J. (1992) · The Journal of comparative neurology · doi:10.1002/cne.903260204 · Cited by 365 · 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
Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants
Browne, C. A., & Lucki, I. (2013) · Frontiers in Pharmacology · doi:10.3389/fphar.2013.00161 · Cited by 285 · see citing works
An excitatory synapse hypothesis of depression
Thompson, S. M., Kallarackal, A. J., Kvarta, M. D., Van Dyke, A. M., LeGates, T. A., & Cai, X. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2015.03.003 · Cited by 265 · see citing works
Self-citationPsychological effects of ketamine in healthy volunteers
Pomarol‐Clotet, E., Honey, G. D., Murray, G. K., Corlett, P. R., Absalom, A. R., Lee, M., McKenna, P. J., Bullmore, E. T., & Fletcher, P. C. (2006) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.105.015263 · Cited by 210 · see citing works
Wolff, K., & WINSTOCK, A. R. (2006) · CNS Drugs · doi:10.2165/00023210-200620030-00003 · Cited by 209 · see citing works
Cornwell, B. R., Salvadore, G., Furey, M., Marquardt, C. A., Brutsché, N. E., Grillon, C., & Zarate, C. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.029 · Cited by 200 · see citing works
The Female Urine Sniffing Test: A Novel Approach for Assessing Reward-Seeking Behavior in Rodents
Malkesman, O., Scattoni, M. L., Paredes, D., Tragon, T. R., Pearson, B. L., Shaltiel, G., Chen, G., Crawley, J. N., & Manji, H. K. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.10.018 · Cited by 197 · see citing works
Ghoneim (1985) · doi:10.1097/00004714-198504000-00003 · Cited by 196 · see citing works
Kallarackal, A. J., Kvarta, M. D., Cammarata, E., Jaberi, L., Cai, X., Bailey, A. M., & Thompson, S. M. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2588-13.2013 · Cited by 181 · see citing works
Self-citationIrifune, M., Shimizu, T., & Nomoto, M. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90571-i · Cited by 162 · see citing works
Koike, H., & Chaki, S. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.05.065 · Cited by 157 · see citing works
RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors
Ballard, T. M., Knoflach, F., Prinssen, E. P. M., Borroni, E., Vivian, J. A., Basile, J., Gasser, R., Moreau, J., Wettstein, J. G., Buettelmann, B., et al. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1357-7 · Cited by 156 · see citing works
Farber, N. B., Newcomer, J. W., & Olney, J. W. (1998) · Progress in brain research · doi:10.1016/s0079-6123(08)60453-7 · Cited by 148 · see citing works
Driesen, N. R., McCarthy, G., Bhagwagar, Z., Bloch, M. H., Calhoun, V. D., D'Souza, D. C., Gueorguieva, R., He, G., Leung, H.-C., Ramani, R., et al. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.170 · Cited by 148 · see citing works
Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine
Mansbach, R. S., & Geyer, M. A. (1991) · Psychopharmacology · doi:10.1007/bf02244303 · Cited by 140 · see citing works
Dwyer, J. M., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.11.011 · Cited by 134 · see citing works
Zanos, P., Georgiou, P., Wright, S. R., Hourani, S. M., Kitchen, I., Winsky-Sommerer, R., & Bailey, A. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.285 · Cited by 133 · see citing works
Self-citationMalherbe, P., Sigel, E., Baur, R., Persohn, E., Richards, J. G., & Möhler, H. (1990) · FEBS Letters · doi:10.1016/0014-5793(90)80118-3 · Cited by 130 · see citing works
Fischell, J., Van Dyke, A. M., Kvarta, M. D., LeGates, T. A., & Thompson, S. M. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.112 · Cited by 122 · see citing works
Self-citationKittelberger, K. A., Hur, E. E., Sazegar, S., Keshavan, V., & Kocsis, B. (2011) · Brain Structure and Function · doi:10.1007/s00429-011-0351-8 · Cited by 120 · see citing works
Morgan, C. J. A., Monaghan, L., & Curran, H. V. (2004) · Addiction · doi:10.1111/j.1360-0443.2004.00879.x · Cited by 113 · see citing works
Middleton, S. J., Jalics, J. Z., Kispersky, T. J., LeBeau, F. E. N., Roopun, A. K., Kopell, N., Whittington, M. A., & Cunningham, M. O. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809302105 · Cited by 113 · see citing works
Zanos, P., Piantadosi, S. C., Wu, H., Pribut, H. J., Dell, M. J., Can, A., Snodgrass, H. R., Zarate, C. A., Schwarcz, R. M., & Gould, T. D. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.225664 · Cited by 111 · see citing works
Self-citationAtack, J. R., Maubach, K. A., Wafford, K. A., O'Connor, D. V., Rodrigues, A. D., Evans, D. C., Tattersall, F. D., Chambers, M. S., MacLeod, A. M., Eng, W., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.157636 · Cited by 72 · see citing works
Hunt, M. J., Falińska, M., Łęski, S., Wojcik, D. K., & Kasicki, S. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881110362126 · Cited by 70 · see citing works
Suzuki, T., Aoki, T., KATO, H. E., et al. (1999) · European Journal of Pharmacology · doi:10.1016/s0014-2999(99)00762-1 · Cited by 35 · see citing works
Efremov, R. G., Feofanov, A. V., Dzhandzhugazyan, K. N., et al. (1990) · FEBS Letters · doi:10.1016/0014-5793(90)80117-2 · Cited by 18 · see citing works
Papazoglou, A., Soós, J., Lundt, A., Wormuth, C., Ginde, V. R., Müller, R., Henseler, C., Broich, K., Xie, K., Ehninger, D., et al. (2016) · Neural Plasticity · doi:10.1155/2016/7167358 · Cited by 16 · see citing works
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- Authors
- Zanos, P., Nelson, M. E., Highland, J. N., Krimmel, S. R., Georgiou, P., Gould, T. D., & Thompson, S. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Thompson, Scott M.
- ORCID
- Venue
- eNeuro
- Publisher
- Society for Neuroscience
- Published
- 2017-01
- Volume
- 4
- Issue
- 1
- Pages
- ENEURO.0285-16.2017
- ISSN
- 2373-2822 (ISSN-L)
- PMC
- PMC5334634
- OpenAlex
- W2590281714
- Cited by
- 106
- References
- 46
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 13 · 2020: 9 · 2019: 25 · 2018: 18 · 2017: 2
- FWCI
- 10.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eNeuro (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- HHS NIH National Institute of Mental Health (NIMH R01 086828, MH R01 107615)
- Kahlert Foundation
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- alpha5 GABA-A receptor, negative allosteric modulators, ketamine, rapid-acting antidepressants, antidepressant side effects, forced swim test, chronic stress, AMPA receptors, NBQX, prepulse inhibition, conditioned place preference, locomotion
- MeSH terms
- Allosteric Regulation, Animals, Antidepressive Agents, Conditioning, Psychological, Depressive Disorder, Disease Models, Animal, Drug Evaluation, Preclinical, Isoxazoles, Ketamine, Male, Mice, Inbred C57BL, Motor Activity, Quinoxalines, Receptors, GABA-A, Triazines, Receptors, AMPA, Excitatory Amino Acid Agents, Prepulse Inhibition, Gamma Rhythm
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