Dopamine Receptor D2 and Associated microRNAs Are Involved in Stress Susceptibility and Resistance to Escitalopram Treatment
Open accessAbstract
BACKGROUND: Early life stress has been demonstrated to increase the risk of developing depression in adulthood. However, the roles and associated molecular mechanisms of stresses in the onset and relapse of depression have yet to be fully elucidated. METHODS: Depression-like behaviors were induced in rats by maternal deprivation and chronic unpredictable stress. Depression- and anxiety-like behaviors of rats, dopamine receptor D2 level, and microRNAs expression in rats' brain tissues were measured. RESULTS: Chronic unpredictable stress alone induced depression-like behaviors in rats, but maternal deprivation enhanced the effect of chronic unpredictable stress. Escitalopram significantly decreased depression-like behaviors in chronic unpredictable stress rats but was less effective in maternal deprivation with chronic unpredictable stress rats. Maternal deprivation increased dopamine receptor D2 messenger RNA expression and decreased microRNA-9 expression in the striatum. Chronic unpredictable stress increased dopamine receptor D2 mRNA and protein levels and decreased microRNA-9 expression in the nucleus accumbens. Furthermore, maternal deprivation enhanced the effect of chronic unpredictable stress on dopamine receptor D2 gene and microRNA-9 expression. Chronic unpredictable stress increased the expression of microRNA-326 in the nucleus accumbens but decreased it in the striatum, whereas maternal deprivation elevated microRNA-326 expression in the striatum. Escitalopram normalized microRNA-326 expression but had no effect on the expression of microRNA-9, dopamine receptor D2 mRNA, and dopamine receptor D2 protein in both the nucleus accumbens and striatum. The in vitro study showed that only microRNA-9 directly targeted the 3' untranslated region of dopamine receptor D2 mRNA and inhibited dopamine receptor D2 protein expression. CONCLUSION: Early life stress enhanced the susceptibility to late life stress and resistance to escitalopram treatment through decreasing microRNA-9 expression and subsequently upregulating dopamine receptor D2 expression in the nucleus accumbens. microRNA-326 may be a novel target of escitalopram.
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miR-326 may be a novel target of escitalopram.
“indicating that miR-326 may be a novel target of escitalopram.335”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [335]
Escitalopram administration for four weeks normalized abnormal levels of miR-326 in the NAc of depressed rats.
“Escitalopram administration for four weeks normalized abnormal levels of miR-326 in the NAc of depressed rats, indicating that miR-326 may be a novel target of escitalopram.335”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [335]
In adult male rats, maternal separation alone or combined with chronic unpredictable stress increases miR-326 in the nucleus accumbens and reduces it in the striatum.
“MiR-326, which has neuron-enriched expression in the neocortex [105, 114, 115] and targets the dopamine D2 receptor [116] was found to be increased in the nucleus accumbens (NAc) and reduced in the striatum of adult male rats exposed to MS alone, and MS combined with maternal chronic unpredictable stress [117].”
From Cell-type-specific epigenetic effects of early life stress on the brain (2022) · cites this paper as [117]
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Cites
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
The role of dopamine in the pathophysiology of depression
Dunlop, B. W., & Nemeroff, C. B. (2007) · Archives of General Psychiatry · doi:10.1001/archpsyc.64.3.327 · Cited by 1,244 · see citing works
Weaver, I. C. G., Champagne, F. A., Brown, S. E., Dymov, S., Sharma, S., Meaney, M. J., & Szyf, M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3652-05.2005 · Cited by 905 · see citing works
Packer, A. N., Xing, Y., Harper, S. Q., Jones, L., & Davidson, B. L. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2390-08.2008 · Cited by 679 · see citing works
miR-29 miRNAs activate p53 by targeting p85α and CDC42
Park, S. Y., Lee, J. H., Ha, M., Nam, J., & Kim, V. N. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1533 · Cited by 608 · see citing works
Preclinical models: status of basic research in depression
Nestler, E. J., Gould, E., & Manji, H. K. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01405-1 · Cited by 559 · see citing works
MiR-16 Targets the Serotonin Transporter: A New Facet for Adaptive Responses to Antidepressants
Baudry, A., Mouillet-Richard, S., Schneider, B., Launay, J.-M., & Kellermann, O. (2010) · Science · doi:10.1126/science.1193692 · Cited by 480 · see citing works
The mesoaccumbens dopamine in coping with stress
Cabib, S., & Puglisi-Allegra, S. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2011.04.012 · Cited by 329 · see citing works
Uchida, S., Hara, K., Kobayashi, A., Funato, H., Hobara, T., Otsuki, K., Yamagata, H., McEwen, B. S., & Watanabe, Y. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1436-10.2010 · Cited by 310 · see citing works
Classification of trauma and stressor-related disorders in DSM-5
Friedman, M. J., Resick, P. A., Bryant, R. A., Strain, J. J., Horowitz, M. J., & Spiegel, D. (2011) · Depression and Anxiety · doi:10.1002/da.20845 · Cited by 254 · see citing works
Changes in Brain MicroRNAs Contribute to Cholinergic Stress Reactions
Meerson, A., Cacheaux, L. P., Goosens, K. A., Sapolsky, R. M., Soreq, H., & Kaufer, D. (2009) · Journal of Molecular Neuroscience · doi:10.1007/s12031-009-9252-1 · Cited by 203 · see citing works
Bai, M., Zhu, X., Zhang, Y., Zhang, S., Zhang, L., Xue, L., Yi, J., Yao, S., & Zhang, X. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046921 · Cited by 195 · see citing works
Self-citationEarly-life stress mediated modulation of adult neurogenesis and behavior
Korosi, A., Naninck, E. F. G., Oomen, C. A., Schouten, M., Krugers, H., Fitzsimons, C., & Lucassen, P. J. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.07.037 · Cited by 194 · see citing works
Clinical and psychometric correlates of dopamine D<sub>2</sub> binding in depression
SHAH, P. J., OGILVIE, A. D., GOODWIN, G. M., & EBMEIER, K. P. (1997) · Psychological Medicine · doi:10.1017/s0033291797005382 · Cited by 170 · see citing works
Lucas, L., Celen, Z., Tamashiro, K. L., Blanchard, R. J., Blanchard, D. C., Markham, C. M., Sakai, R. R., & McEwen, B. S. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2003.12.009 · Cited by 145 · see citing works
O’Connor, R. M., Dinan, T. G., & Cryan, J. F. (2011) · Molecular Psychiatry · doi:10.1038/mp.2011.162 · Cited by 133 · see citing works
Differential Allelic Expression of Dopamine D1 Receptor Gene (DRD1) Is Modulated by microRNA miR-504
Huang, W., & Li, M. D. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.11.024 · Cited by 121 · see citing works
Lin, Y., Liu, A., Xu, Y., Tie, L., Yu, H., & Li, X.-J. (2005) · Behavioural Brain Research · doi:10.1016/j.bbr.2005.06.034 · Cited by 108 · see citing works
Kirino, E. (2012) · Patient Preference and Adherence · doi:10.2147/ppa.s22495 · Cited by 93 · see citing works
The pathways from mother's love to baby's future
Kőrösi, A. (2009) · Frontiers in Behavioral Neuroscience · doi:10.3389/neuro.08.027.2009 · Cited by 92 · see citing works
Zhang, Y., Zhu, X., Bai, M., Zhang, L., Xue, L., & Yi, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069934 · Cited by 83 · see citing works
Self-citationBasso, A. M., Gallagher, K. B., Bratcher, N. A., Brioni, J. D., Moreland, R. B., Hsieh, G. C., Drescher, K. U., Fox, G. B., Decker, M. W., & Rueter, L. E. (2005) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300677 · Cited by 79 · see citing works
Zhang, X., Lee, T. H., Davidson, C., Lazarus, C., Wetsel, W. C., & Ellinwood, E. H. (2006) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301101 · Cited by 72 · see citing works
Self-citationNormal Midbrain Dopaminergic Neuron Development and Function in miR-133b Mutant Mice
Heyer, M. P., Pani, A. K., Smeyne, R. J., Kenny, P. J., & Feng, G. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1732-12.2012 · Cited by 71 · see citing works
Monroe, S. M., Torres, L. D., Guillaumot, J., Harkness, K. L., Roberts, J. E., Frank, E., & Kupfer, D. J. (2006) · Journal of Consulting and Clinical Psychology · doi:10.1037/0022-006x.74.1.112 · Cited by 57 · see citing works
Electroconvulsive Therapy Alters Dopamine Signaling in the Striatum of Non-human Primates
Landau, A. M., Chakravarty, M. M., Clark, C. M., Zis, A. P., & Doudet, D. J. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.182 · Cited by 57 · see citing works
Stress-induced depressive behaviors are correlated with Par-4 and DRD2 expression in rat striatum
Zhu, X., Peng, S., Zhang, S., & Zhang, X. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.052 · Cited by 45 · see citing works
Self-citationDaws, S. E., Black, Y. D., Naydenov, A. V., Vassoler, F. M., Hanlin, R. P., & Konradi, C. L. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.03.035 · Cited by 25 · see citing works
Cocaine sensitization models an anhedonia-like condition in rats
Scheggi, S., Marchese, G., Grappi, S., Secci, M. E., Montis, M. G. D., & Gambarana, C. (2010) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145710000532 · Cited by 22 · see citing works
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Cited by
Sorted by citations
Yuan, M., Yang, B., Rothschild, G., Mann, J. J., Sanford, L. D., Tang, X., Huang, C., Wang, C., & Zhang, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01519-z · Cited by 246 · see citing works
“Escitalopram administration for four weeks normalized abnormal levels of miR-326 in the NAc of depressed rats, indicating that miR-326 may be a novel target of escitalopram.(335) The problem with most studies is that they cannot distinguish between miRNA normalization as part of the antidepressant action or miRNA norm…”
BackgroundZhang, Y., Du, L., Bai, Y., Han, B., He, C., Gong, L., Huang, R., Shen, L., Chao, J., Liu, P., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-018-0285-0 · Cited by 184 · see citing works
Self-citationEpigenetic programming by stress and glucocorticoids along the human lifespan
Zannas, A. S., & Chrousos, G. P. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.35 · Cited by 158 · 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
Cell-type-specific epigenetic effects of early life stress on the brain
Rahman, M. F., & McGowan, P. O. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02076-9 · Cited by 75 · see citing works
Ignácio, Z. M., Réus, G. Z., Abelaira, H. M., Maciel, A. L., de Moura, A. B., Matos, D., Demo, J. P., da Silva, J. B. I., Gava, F. F., Valvassori, S. S., et al. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.11.044 · Cited by 53 · see citing works
The importance of epigenetics in diagnostics and treatment of major depressive disorder
Czarny, P., Białek, K., Ziółkowska, S., Strycharz, J., Barszczewska, G., & Sliwinski, T. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11030167 · Cited by 37 · see citing works
Bortolozzi, A., Manashirov, S., Chen, A., & Artigas, F. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107873 · Cited by 37 · see citing works
miRNAs in depression vulnerability and resilience: novel targets for preventive strategies
Lopizzo, N., Zonca, V., Cattane, N., Pariante, C. M., & Cattaneo, A. (2019) · Journal of Neural Transmission · doi:10.1007/s00702-019-02048-2 · Cited by 37 · see citing works
Epigenetic Mechanisms of Rapid-Acting Antidepressants
Inserra, A., Campanale, A., Rezai, T., Romualdi, P., & Rubino, T. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03055-y · Cited by 27 · see citing works
- Authors
- Zhang, Y., Wang, Y., Wang, L., Bai, M., Zhang, X., & Zhu, X.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Zhu, X.
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-03-03
- Volume
- 18
- Issue
- 8
- Pages
- pyv025-pyv025
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC4571637
- OpenAlex
- W2095128214
- Cited by
- 104
- References
- 29
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 11 · 2023: 17 · 2022: 12 · 2021: 14 · 2020: 5 · 2019: 11 · 2018: 6 · 2017: 10 · 2016: 7 · 2015: 1
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Natural Science Foundation of China (81071097)
- Hunan Provincial Innovation Foundation for Postgraduate
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- dopamine D2 receptor, miR-9, early life stress, maternal deprivation, chronic unpredictable mild stress, depression, escitalopram, antidepressant resistance, nucleus accumbens, striatum, 3' untranslated region, microRNA target regulation, depression-like behavior, anxiety-like behavior
- MeSH terms
- Animals, Chronic Disease, Corpus Striatum, Depressive Disorder, Disease Models, Animal, Drug Resistance, Male, Maternal Deprivation, Nucleus Accumbens, Random Allocation, RNA, Messenger, Stress, Psychological, Citalopram, Rats, Sprague-Dawley, Receptors, Dopamine D2, Antidepressive Agents, Second-Generation, Uncertainty, MicroRNAs, Depressive Disorder, Treatment-Resistant
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