Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors
Open accessAbstract
Clinical studies demonstrate that scopolamine, a non-selective muscarinic acetylcholine receptor (mAchR) antagonist, produces rapid therapeutic effects in depressed patients, and preclinical studies report that the actions of scopolamine require glutamate receptor activation and the mechanistic target of rapamycin complex 1 (mTORC1). The present study extends these findings to determine the role of the medial prefrontal cortex (mPFC) and specific muscarinic acetylcholine receptor (M-AchR) subtypes in the actions of scopolamine. The administration of scopolamine increases the activity marker Fos in the mPFC, including the infralimbic (IL) and prelimbic (PrL) subregions. Microinfusions of scopolamine into either the IL or the PrL produced significant antidepressant responses in the forced swim test, and neuronal silencing of IL or PrL blocked the antidepressant effects of systemic scopolamine. The results also demonstrate that the systemic administration of a selective M1-AChR antagonist, VU0255035, produced an antidepressant response and stimulated mTORC1 signaling in the PFC, similar to the actions of scopolamine. Finally, we used a chronic unpredictable stress model as a more rigorous test of rapid antidepressant actions and found that a single dose of scopolamine or VU0255035 blocked the anhedonic response caused by CUS, an effect that requires the chronic administration of typical antidepressants. Taken together, these findings indicate that mPFC is a critical mediator of the behavioral actions of scopolamine and identify the M1-AChR as a therapeutic target for the development of novel and selective rapid-acting antidepressants.
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Ketamine and other fast-acting agents rapidly reverse the synaptic deficits caused by chronic stress exposure and by depression.
“Moreover, ketamine and other fast-acting agents rapidly reverse the synaptic deficits caused by chronic stress exposure and by depression, demonstrating that agents such as ketamine can rapidly reverse the pathophysiology of depression (8, 46).”
From Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation (2019) · cites this paper as [46]
A selective muscarinic 1 antagonist produces antidepressant actions similar to scopolamine in rodent models.
“Studies to identify the receptor subtype indicate that a selective muscarinic 1 antagonist produces antidepressant actions similar to scopolamine in rodent models173,174.”
From Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants (2016) · cites this paper as [173]
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Cites
The rat brain in stereotaxic coordinates
Palkovits, M. (1983) · Neuropeptides · doi:10.1016/0143-4179(83)90049-5 · Cited by 28,959 · see citing works
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585 · see citing works
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
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K. R., Rush, A. J., Walters, E. E., & Wang, P. S. (2003) · JAMA · doi:10.1001/jama.289.23.3095 · Cited by 7,988 · see citing works
Antidepressant 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
Self-citationDrevets, W. C., Price, J. L., & Furey, M. L. (2008) · Brain Structure and Function · doi:10.1007/s00429-008-0189-x · Cited by 2,209 · see citing works
Antidepressant Drug Effects and Depression Severity: A Patient-Level Meta-analysis
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010) · JAMA · doi:10.1001/jama.2009.1943 · Cited by 2,009 · see citing works
Willner, P., Towell, A., Sampson, D., Sophokleous, S., & Muscat, R. (1987) · Psychopharmacology · doi:10.1007/bf00187257 · Cited by 1,993 · see citing works
Expression of c- <i>fos</i> Protein in Brain: Metabolic Mapping at the Cellular Level
Sagar, S. M., Sharp, F. R., & Curran, T. (1988) · Science · doi:10.1126/science.3131879 · Cited by 1,925 · see citing works
Willner, P. (1997) · Psychopharmacology · doi:10.1007/s002130050456 · Cited by 1,832 · 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 · cited 1× · see citing works
“Recent mechanistic studies in rodent models have demonstrated similarities in the downstream cellular actions underlying the rapid antidepressant effects of ketamine and scopolamine (Duman and Aghajanian, 2012; Li et al., 2010, 2011; Voleti et al., 2013).”
BackgroundSelf-citationHypothalamic mTOR Signaling Regulates Food Intake
Cota, D., Proulx, K., Smith, K. A. B., Kozma, S. C., Thomas, G., Woods, S. C., & Seeley, R. J. (2006) · Science · doi:10.1126/science.1124147 · Cited by 1,278 · see citing works
Sierra-Mercado, D., Padilla-Coreano, N., & Quirk, G. J. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.184 · Cited by 1,190 · 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-citationRepeated Stress Induces Dendritic Spine Loss in the Rat Medial Prefrontal Cortex
Radley, J. J., Rocher, A. B., Miller, M., Janssen, W. G. M., Liston, C., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhi104 · Cited by 820 · see citing works
Radley, J. J., Sisti, H. M., Hao, J., Rocher, A. B., McCall, T., Hof, P. R., McEwen, B. S., & Morrison, J. H. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.01.006 · Cited by 769 · see citing works
Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress.
Ceccatelli, S., Villar, M. J., Goldstein, M., & Hökfelt, T. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.23.9569 · Cited by 536 · see citing works
Wilensky, A. E., Schafe, G. E., Kristensen, M. P., & LeDoux, J. E. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4316-06.2006 · Cited by 533 · see citing works
Furey, M. L., & Drevets, W. C. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.10.1121 · Cited by 417 · see citing works
Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond
Krystal, J. H., Sanacora, G., & Duman, R. S. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.03.026 · Cited by 406 · see citing works
Self-citationLiu, R.-J., & Aghajanian, G. K. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706679105 · Cited by 346 · see citing works
Laurent, V., & Westbrook, R. F. (2009) · Learning & Memory · doi:10.1101/lm.1474609 · Cited by 311 · see citing works
Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice.
Pitler, T. A., & Alger, B. E. (1992) · The Journal of Physiology · doi:10.1113/jphysiol.1992.sp019119 · Cited by 288 · see citing works
MacQueen, G. M., Yucel, K., Taylor, V. H., Macdonald, K., & Joffe, R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.06.027 · Cited by 274 · see citing works
Fuchikami, M., Thomas, A., Liu, R., Wohleb, E. S., Land, B. B., DiLeone, R. J., Aghajanian, G. K., & Duman, R. S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414728112 · Cited by 265 · see citing works
Self-citationVoleti, 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-citationAnatomical Markers of Activity in Neuroendocrine Systems: Are we all ‘Fos‐ed out’?
Hoffman, G. E., & Lyo, D. (2002) · Journal of Neuroendocrinology · doi:10.1046/j.1365-2826.2002.00775.x · Cited by 242 · see citing works
Drevets, W. C., & Furey, M. L. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.11.021 · Cited by 241 · see citing works
Cholinergic modulation of the cortical neuronal network
Lucas-Meunier, E., Fossier, P., Baux, G., & Amar, M. (2003) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-002-0999-2 · Cited by 207 · see citing works
Antidepressant Effects of Fibroblast Growth Factor-2 in Behavioral and Cellular Models of Depression
Elsayed, M., Banasr, M., Duric, V., Fournier, N. M., Licznerski, P., & Duman, R. S. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.003 · Cited by 169 · see citing works
Self-citationSheffler, D. J., Williams, R. D., Bridges, T. M., Xiang, Z., Kane, A. S., Byun, N. E., Jadhav, S. B., Mock, M. M., Zheng, F., Lewis, L. M., et al. (2009) · Molecular Pharmacology · doi:10.1124/mol.109.056531 · Cited by 134 · 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 100 · see citing works
Golding, J. F., & Stott, J. R. R. (1997) · British Journal of Clinical Pharmacology · doi:10.1046/j.1365-2125.1997.00606.x · Cited by 99 · see citing works
Moriya, H., Takagi, Y., Nakanishi, T., et al. (1999) · Life Sciences · doi:10.1016/s0024-3205(99)00188-5 · Cited by 94 · see citing works
Roldán, G., Bolaños-Badillo, E., González-Sánchez, H., et al. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00489-8 · Cited by 83 · see citing works
Xiang, Z., Thompson, A. D., Jones, C. K., Lindsley, C. W., & Conn, P. J. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.187856 · Cited by 74 · see citing works
McQuiston, A. R., & Madison, D. V. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05703.1999 · Cited by 67 · see citing works
Medalla, M., & Barbas, H. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2339-12.2012 · Cited by 57 · see citing works
Limitations of contemporary antidepressants: tolerability.
Papakostas, G. I. (2007) · PubMed · Cited by 39 · see citing works
A sensitive double immunostaining protocol for Fos-immunoreactive neurons
Peng, Z.-C., Chen, S., & Bentivoglio, M. (1995) · Brain Research Bulletin · doi:10.1016/0361-9230(94)00125-k · Cited by 19 · see citing works
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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
Self-citationIntegrating neuroimmune systems in the neurobiology of depression
Wohleb, E. S., Franklin, T., Iwata, M., & Duman, R. S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.69 · Cited by 668 · see citing works
Self-citationWidman, A. J., & McMahon, L. L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718883115 · Cited by 204 · see citing works
Fukumoto, K., Fogaça, M. V., Liu, R.-J., Duman, C., Kato, T., Li, X.-Y., & Duman, R. S. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1814709116 · Cited by 188 · see citing works
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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
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Wohleb, E. S., Wu, M., Gerhard, D. M., Taylor, S. R., Picciotto, M. R., Alreja, M., & Duman, R. S. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85033 · Cited by 144 · see citing works
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Gould, T. D., Zarate, C. A., & Thompson, S. M. (2019) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010617-052811 · Cited by 133 · see citing works
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Kim, J.-W., Autry, A. E., Na, E. S., Adachi, M., Björkholm, C., Kavalali, E. T., & Monteggia, L. M. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00868-8 · Cited by 113 · see citing works
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Wallace, T., & Myers, B. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.737960 · Cited by 8 · see citing works
- Authors
- Navarria, A., Wohleb, E. S., Voleti, B., Ota, K. T., Dutheil, S., Lepack, A. E., Dwyer, J. M., Fuchikami, M., Becker, A., Drago, F., & Duman, R. S.
- Affiliations
- Yale University (US)
- University of Catania (IT)
- Corresponding author
- Duman, Ronald S.
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 82
- Pages
- 254-261
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC4640941
- OpenAlex
- W850398009
- Cited by
- 118
- References
- 43
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 15 · 2020: 16 · 2019: 10 · 2018: 16 · 2017: 16 · 2016: 8 · 2015: 1
- FWCI
- 9.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (MH093897)
- State of Connecticut
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- scopolamine, rapid-acting antidepressants, medial prefrontal cortex, M1 muscarinic receptor, antimuscarinic agents, infralimbic cortex, prelimbic cortex, mTORC1 signaling, Fos expression, forced swim test, chronic unpredictable mild stress, anhedonia, depression
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Antidepressive Agents, Chronic Disease, Disease Models, Animal, Male, Microinjections, Scopolamine, Stress, Psychological, Sulfonamides, Thiadiazoles, Time Factors, Signal Transduction, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Prefrontal Cortex, Muscarinic Antagonists, Dietary Sucrose, Receptor, Muscarinic M1, Tissue Culture Techniques, Multiprotein Complexes, TOR Serine-Threonine Kinases, Anhedonia
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