Kappa Opioid Receptor Activation Induces Epigenetic Silencing of Brain-Derived Neurotropic Factor via HDAC5 in Depression
Open accessPublished version of a preprint
Abstract
Treatment-resistant depression (TRD) occurs in almost 50% of the depressed patients. Central kappa opioid receptor (KOR) agonism has been demonstrated to induce depression and anxiety, while KOR antagonism alleviates depression-like symptoms in rodent models and TRD in clinical studies. Previously, we have shown that sustained KOR activation leads to a TRD-like phenotype in mice, and modulation of brain-derived neurotrophic factor (BDNF) expression in the prefrontal cortex (PFC) appears to be one of the molecular determinants of the antidepressant response. In the present study, we observed that sustained KOR activation by a selective agonist, U50488, selectively reduced the levels of Bdnf transcripts II, IV, and Bdnf CDS (protein-coding Exon IX) in the PFC and cultured primary cortical neurons, which was blocked by selective KOR antagonist, norbinaltorphimine . Considering the crucial role of epigenetic pathways in BDNF expression, we further investigated the role of various epigenetic markers in KOR-induced BDNF downregulation in mice. We observed that treatment with U50488 resulted in selective and specific downregulation of acetylation at the ninth lysine residue of the histone H3 protein (H3K9ac) and upregulation of histone deacetylase 5 (HDAC5) expression in the PFC. Further, using anti-H3K9ac and anti-HDAC5 antibodies in the chromatin immune precipitation assay, we detected decreased enrichment of H3K9ac and increased HDAC5 binding at Bdnf II and IV transcripts after U50488 treatment, which were blocked by a selective KOR antagonist, norbinaltorphimine . Further mechanistic studies using HDAC5 selective inhibitor, LMK235, in primary cortical neurons and adeno-associated viral shRNA-mediated HDAC5-knockdown in the PFC of mice demonstrated an essential role of HDAC5 in KOR-mediated reduction of Bdnf expression in the PFC and in depression-like symptoms in mice. These results suggest that KOR engages multiple pathways to induce depression-like symptoms in mice and provide novel insights into the mechanisms by which activation of KOR regulates major depressive disorders.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Changes in histone marks are linked to neuroinflammation and neuronal injury, contributing to structural and functional alterations observed in depression.
“Changes in histone marks have been linked to neuroinflammation and neuronal injury, contributing to structural and functional alterations observed in depression (Yadav et al., 2024; Yuan et al., 2023; Zhu et al., 2021).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Yadav et al., 2024
Cites
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217 · see citing works
Neurotrophin regulation of neural circuit development and function
Park, H., & Poo, M.-M. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3379 · Cited by 2,060 · see citing works
Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action
Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006) · Nature Neuroscience · doi:10.1038/nn1659 · Cited by 1,780 · see citing works
Self-citationSynaptic plasticity and depression: new insights from stress and rapid-acting antidepressants
Duman, R. S., Aghajanian, G. K., Sanacora, G., & Krystal, J. H. (2016) · Nature Medicine · doi:10.1038/nm.4050 · Cited by 1,750 · see citing works
HDAC2 negatively regulates memory formation and synaptic plasticity
Guan, J.-S., Haggarty, S. J., Giacometti, E., Dannenberg, J.-H., Joseph, N., Gao, J., Nieland, T. J. F., Zhou, Y., Wang, X., Mazitschek, R., et al. (2009) · Nature · doi:10.1038/nature07925 · Cited by 1,644 · see citing works
Calcium regulation of neuronal gene expression
West, A. E., Chen, W. G., Dalva, M., Dolmetsch, R., Kornhauser, J., Shaywitz, A. J., Takasu, M., Tao, X., & Greenberg, M. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.191352298 · Cited by 1,115 · see citing works
BDNF - a key transducer of antidepressant effects
Björkholm, C., & Monteggia, L. M. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.10.034 · Cited by 958 · see citing works
Mouse and rat <i>BDNF</i> gene structure and expression revisited
Aid, T., Kazantseva, A., Piirsoo, M., Palm, K., & Timmusk, T. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21139 · Cited by 943 · see citing works
Canuso, C. M., Singh, J. B., Fedgchin, M., Alphs, L., Lane, R., Lim, P., Pinter, C., Hough, D., Sanacora, G., Manji, H., et al. (2018) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2018.17060720 · Cited by 676 · see citing works
Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli
Renthal, W., Maze, I., Krishnan, V., Covington, H. E., Xiao, G., Kumar, A., Russo, S. J., Graham, A., Tsankova, N., Kippin, T. E., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.09.032 · Cited by 599 · see citing works
Self-citationValasek, M. A., & Repa, J. J. (2005) · AJP Advances in Physiology Education · doi:10.1152/advan.00019.2005 · Cited by 594 · see citing works
HDAC4 deacetylase associates with and represses the MEF2 transcription factor
Miska, E. A., Karlsson, C., Langley, E., Nielsen, S. J., Pines, J., & Kouzarides, T. (1999) · The EMBO Journal · doi:10.1093/emboj/18.18.5099 · Cited by 551 · see citing works
Lu, J., McKinsey, T. A., Zhang, C., & Olson, E. N. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00025-3 · Cited by 547 · see citing works
Lu, J., McKinsey, T. A., Nicol, R. L., & Olson, E. N. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.080064097 · Cited by 518 · 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
Treatment resistant depression: A multi-scale, systems biology approach
Akil, H., Gordon, J. A., Hen, R., Javitch, J. A., Mayberg, H. S., McEwen, B. S., Meaney, M. J., & Nestler, E. J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.08.019 · Cited by 443 · see citing works
Backs, J., Backs, T., Neef, S., Kreußer, M. M., Lehmann, L., Patrick, D. M., Grueter, C. E., Qi, X., Richardson, J. A., Hill, J. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813013106 · Cited by 431 · see citing works
Untangling the complexity of opioid receptor function
Valentino, R. J., & Volkow, N. D. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0225-3 · Cited by 383 · see citing works
BDNF mechanisms in late LTP formation: A synthesis and breakdown
Panja, D., & Bramham, C. R. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.06.024 · Cited by 336 · see citing works
The role of histone modifications: from neurodevelopment to neurodiseases
Park, J., Lee, K., Kim, K., & Yi, S.-J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01078-9 · Cited by 321 · see citing works
Neuronal activity‐dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5
Chawla, S., Vanhoutte, P., Arnold, F. J. L., Huang, C. L.-H., & Bading, H. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01648.x · Cited by 301 · see citing works
Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine
Liu, Q., Lü, L., Zhu, X.-G., Gong, J.-P., Shaham, Y., & Uhl, G. R. (2005) · Brain Research · doi:10.1016/j.brainres.2005.10.004 · Cited by 297 · see citing works
Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation
Ramamoorthi, K., Fropf, R., Belfort, G. M., Fitzmaurice, H. L., McKinney, R. M., Neve, R. L., Otto, T., & Lin, Y. (2011) · Science · doi:10.1126/science.1208049 · Cited by 295 · see citing works
Ghosal, S., Hare, B. D., & Duman, R. S. (2016) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2016.09.012 · Cited by 203 · see citing works
Sakata, K., Woo, N. H., Martinowich, K., Greene, J. S., Schloesser, R. J., Shen, L., & Lu, B. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811431106 · Cited by 200 · see citing works
Baj, G., Leone, E., Chao, M. V., & Tongiorgi, E. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014168108 · Cited by 196 · see citing works
Delving deeper into resistance
Seton-Rogers, S. E. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3653 · Cited by 194 · see citing works
Nair, A., Vadodaria, K. C., Banerjee, S. B., Benekareddy, M., Dias, B. G., Duman, R. S., & Vaidya, V. A. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301276 · Cited by 189 · see citing works
Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches
Peciña, M., Karp, J. F., Mathew, S. J., Todtenkopf, M. S., Ehrich, E. W., & Zubieta, J.-K. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0117-2 · Cited by 188 · see citing works
Fuchikami, M., Morinobu, S., Kurata, A., Yamamoto, S., & Yamawaki, S. (2008) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145708008997 · Cited by 178 · see citing works
Tadić, A., Müller-Engling, L., Schlicht, K. F., Kotsiari, A., Dreimüller, N., Kleimann, A., Bleich, S., Lieb, K., & Frieling, H. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.58 · Cited by 175 · see citing works
Pharmacological Treatments for Patients with Treatment-Resistant Depression
Ruberto, V. L., Jha, M. K., & Murrough, J. W. (2020) · Pharmaceuticals · doi:10.3390/ph13060116 · Cited by 152 · see citing works
The multiple facets of opioid receptor function: implications for addiction
Lutz, P.-É., & Kieffer, B. L. (2013) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2013.02.005 · Cited by 131 · see citing works
Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion
Chefer, V. I., Bäckman, C. M., Gigante, E. D., & Shippenberg, T. S. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.171 · Cited by 122 · see citing works
Timmusk, T., Lendahl, U., Funakoshi, H., Arenas, E., Persson, H., & METSIS, M. L. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.128.1.185 · Cited by 121 · see citing works
Kronman, H., Torres-Berrío, A., Sidoli, S., Issler, O., Godino, A., Ramakrishnan, A., Mews, P., Lardner, C. K., Parise, E. M., Walker, D. M., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00814-8 · Cited by 108 · see citing works
Pizzagalli, D. A., Smoski, M. J., Ang, Y., Whitton, A. E., Sanacora, G., Mathew, S. J., Nürnberger, J. I., Lisanby, S. H., Iosifescu, D. V., Murrough, J. W., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-020-0738-4 · Cited by 104 · see citing works
Neurotrophins: Transcription and Translation
West, A. E., Pruunsild, P., & Timmusk, T. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-45106-5_4 · Cited by 103 · see citing works
The opioid system in depression
Jelen, L. A., Stone, J. M., Young, A. H., & Mehta, M. A. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104800 · Cited by 102 · see citing works
Hypothalamic leptin action is mediated by histone deacetylase 5
Kabra, D. G., Pfuhlmann, K., García‐Cáceres, C., Schriever, S. C., Casquero-García, V., Kebede, A. F., Fuente-Martín, E., Trivedi, C. J., Heppner, K. M., Uhlenhaut, N. H., et al. (2016) · Nature Communications · doi:10.1038/ncomms10782 · Cited by 93 · see citing works
Meylan, E. M., Halfon, O., Magistretti, P. J., & Cardinaux, J.-R. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.012 · Cited by 87 · see citing works
BDNF genetic variants and methylation: effects on cognition in major depressive disorder
Ferrer, A., Labad, J., Salvat-Pujol, N., Barrachina, M., Costas, J., Urretavizcaya, M., de Arriba-Arnau, A., Crespo, J. M., Soriano-Mas, C., Carracedo, Á., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0601-8 · Cited by 84 · see citing works
D, M. F. M., Thase, M. E., Trivedi, M. H., Ehrich, E. W., Martin, W. F., Memisoglu, A., Nangia, N., Stanford, A. D., Yu, M., & Pathak, S. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0284-1 · Cited by 83 · see citing works
de Carvalho-Netto, E. F., Myers, B., Jones, K., Solomon, M. B., & Herman, J. P. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.01.024 · Cited by 80 · see citing works
Choi, M., Lee, S. H., Wang, S. E., Ko, S. Y., Song, M., Choi, J.-S., Kim, Y.-S., Duman, R. S., & Son, H. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1513913112 · Cited by 78 · see citing works
Ketamine for Depression, 3: Does Chirality Matter?: (Clinical and Practical Psychopharmacology)
Andrade, C. (2017) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.17f11681 · Cited by 78 · see citing works
Sartor, G. C., Malvezzi, A. M., Kumar, A., Andrade, N. S., Wiedner, H. J., Vilca, S. J., Janczura, K. J., Bagheri, A., Al‐Ali, H., Powell, S. K., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1604-18.2018 · Cited by 77 · see citing works
Self-citationSchmauss, C. (2015) · Scientific Reports · doi:10.1038/srep08171 · Cited by 70 · see citing works
Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders
Jacobson, M. L., Browne, C. A., & Lucki, I. (2020) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023317 · Cited by 70 · see citing works
Lyons, M. R., Schwarz, C. M., & West, A. E. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0534-12.2012 · Cited by 64 · see citing works
Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides.
Hercher, C., Canetti, L., Turecki, G., & Mechawar, N. (2010) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2009.08.011 · Cited by 64 · see citing works
Oh, H., Piantadosi, S. C., Rocco, B. R., Lewis, D. A., Watkins, S. C., & Sibille, E. L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.09.026 · Cited by 55 · see citing works
Tissue-specific and neural activity-regulated expression of human BDNF gene in BAC transgenic mice
Koppel, I., Aid‐Pavlidis, T., Jaanson, K., Sepp, M., Pruunsild, P., Palm, K., & Timmusk, T. (2009) · BMC Neuroscience · doi:10.1186/1471-2202-10-68 · Cited by 45 · see citing works
Choi, M., Lee, S. H., Park, M. H., Kim, Y.-S., & Son, H. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.05.157 · Cited by 42 · see citing works
Epigenetic perspective on the role of brain-derived neurotrophic factor in burnout
Bakusic, J., Ghosh, M., Polli, A., Bekaert, B., Schaufeli, W. B., Claes, S. J., & Godderis, L. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-01037-4 · Cited by 28 · see citing works
Dogra, S., Kumar, A., Umrao, D., Sahasrabuddhe, A. A., & Yadav, P. N. (2016) · Scientific Reports · doi:10.1038/srep33401 · Cited by 27 · see citing works
Self-citationD, M. F. M., Mazzone, E., Freeman, M. P., Flynn, M., Judge, H., Hoeppner, B. B., Hock, R. S., Shui, A. M., Macaluso, M., Morrison, M. F., et al. (2020) · Annals of Clinical Psychiatry · doi:10.12788/acp.0003 · Cited by 19 · see citing works
Muñoz-Cobo, I., Erburu, M. M., Zwergel, C., Cirilli, R., Mai, A., Valente, S., Puerta, E., & Tordera, R. M. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4975-8 · Cited by 15 · see citing works
Two tales concerning skeletal muscle
Glass, D. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci33379 · Cited by 13 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Endogenous opiates and behavior: 2024
Bodnar, R. J. (2025) · Peptides · doi:10.1016/j.peptides.2025.171422 · Cited by 5 · see citing works
Lv, L.-Z., Wang, Z.-D., Ren, J.-J., Li, L.-H., Liu, X.-B., Li, J.-L., Zhu, H., Jiang, B., Han, Y.-P., Zhou, X.-M., et al. (2026) · Frontiers in Genetics · doi:10.3389/fgene.2025.1722453 · Cited by 7 · see citing works
Kaito, D., Tamura, T., Suzuki, S., Onishi, R., Tanaka, K. F., Yoshino, J., Matsuoka, T., Maeshima, K., Sasaki, J., & Homma, K. (2025) · PLoS ONE · doi:10.1371/journal.pone.0334608 · Cited by 3 · see citing works
Epigenetic, neuroplasticity, and adrenergic targets associated with major depression in immune cells
Cortés-Erice, M., Garayo, A., Fernández-Ovejero, R., Aubá, E., Lizaso, S., Aldaz, P., Bes‐Rastrollo, M., Gil, J. L., Barrado, L., Ortuño, F., et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-36954-9 · Cited by 3 · see citing works
Structuring the GPCR Story Through the Lens of NMR
Prasad, A., Anjum, Z. I., & Kumar, A. (2025) · Magnetic Resonance in Chemistry · doi:10.1002/mrc.70028 · Cited by 1 · see citing works
Self-citationKappa opioid receptor antagonism in neuropsychiatry: from molecular mechanisms to clinical prospects
Wang, H., Ji, Y., Huang, J., Yang, S., Zhang, Q., Hu, S., Xu, X., & Yang, C. (2026) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-026-02216-y · Cited by 1 · see citing works
Epigenetic, neuroplasticity, and adrenergic targets associated with major depression in immune cellsPreprint
Cortés-Erice, M., Garayo, A., Fernández-Ovejero, R., Aubá, E., Lizaso, S., Aldaz, P., Bes‐Rastrollo, M., Gil, J. L., Barrado, L., Ortuño, F., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-7178520/v1
Gu, J., Hong, J., Lu, X., Liu, N., Lu, H., Tong, L., Liu, H., Zhang, Y., & Huang, C. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04813-8
Ciotei, C., Păunescu, H., Lungu, C., Marica, A., Tănase, M. F., Marin, R., Costescu, M., Fulga, I., & Coman, O. A. (2026) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.71392
- Authors
- Yadav, A., Dogra, S., Boda, A. K., Kumari, P., Kumar, A., Dash, M. K., & Yadav, P. N.
- Affiliations
- Central Drug Research Institute (IN)
- Corresponding author
- Yadav, Prem N.
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2024-08-27
- Volume
- 15
- Issue
- 18
- Pages
- 3286-3297
- ISSN
- 1948-7193 (ISSN-L)
- OpenAlex
- W4401906783
- Cited by
- 9
- References
- 59
- Citations by year
- 2026: 5 · 2025: 4
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Council of Scientific and Industrial Research, India (MLP2032)
- University Grants Commission
- Science and Engineering Research Board (GAP0397)
- Academy of Scientific and Innovative Research (Ghaziabad-201002)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- kappa opioid receptor, treatment-resistant depression, brain-derived neurotrophic factor, HDAC5, epigenetic silencing, H3K9 acetylation, prefrontal cortex, U50,488, nor-binaltorphimine, BDNF isoforms, cortical neurons, depression-like behavior
- MeSH terms
- Animals, Depression, Histone Deacetylases, Male, Mice, Inbred C57BL, Neurons, Prefrontal Cortex, Receptors, Opioid, kappa, Brain-Derived Neurotrophic Factor, 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer, Epigenesis, Genetic, Mice
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
