Amitriptyline up‐regulates connexin43‐gap junction in rat cultured cortical astrocytes via activation of the p 38 and c‐Fos/AP‐1 signalling pathway
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Background and Purpose: Intercellular communication via gap junctions, comprised of connexin (Cx) proteins, allow for communication between astrocytes, which in turn is crucial for maintaining CNS homeostasis. The expression of Cx 43 is decreased in post‐mortem brains from patients with major depression. A potentially novel mechanism of tricyclic antidepressants is to increase the expression and functioning of gap junctions in astrocytes. Experimental Approach: The effect of amitriptyline on the expression of Cx 43 and gap junction intercellular communication (GJIC) in rat primary cultured cortical astrocytes was investigated. We also investigated the role of p 38 MAPK intracellular signalling pathway in the amitriptyline‐induced expression of Cx 43 and GJIC. Key Results: Treatment with amitriptyline for 48 h significantly up‐regulated Cx 43 mRNA, protein and GJIC. The up‐regulation of Cx 43 was not monoamine‐related since noradrenaline, 5‐HT and dopamine did not induce Cx 43 expression and pretreatment with α‐ and β‐adrenoceptor antagonists had no effect. Intracellular signalling involved p 38 MAPK, as amitriptyline significantly increased p 38 MAPK phosphorylation and Cx 43 expression and GJIC were significantly blocked by the p 38 inhibitor SB 202190. Furthermore, amitriptyline‐induced Cx 43 expression and GJIC were markedly reduced by transcription factor AP‐1 inhibitors (curcumin and tanshinone IIA). The translocation of c‐Fos from the cytosol and the nucleus of cortical astrocytes was increased by amitriptyline, and this response was dependent on p 38 activity. Conclusion and Implication: These findings indicate a novel mechanism of action of amitriptyline through cortical astrocytes, and further suggest that targeting this mechanism could lead to the development of a new class of antidepressants.
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Amitriptyline can increase the expression of Cx43 to promote gap junction intercellular communication between astrocytes, thereby relieving depressive symptoms.
“In addition, amitriptyline can increase the expression of Cx43 to promote gap junction intercellular communication (GJIC) between astrocytes, thereby relieving depressive symptoms. 355”
From Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024) · cites this paper as [355]
The Discussion reports that amitriptyline increased Cx43 expression and gap-junction communication in cultured rat cortical astrocytes. The passage under Figure 4 proposes that this could improve depressive symptoms, but says in vivo experiments are needed to confirm that mechanism. The claim presents symptom relief as established rather than hypothetical. (LLM, conf=0.88)
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“355 This suggests that TCAs may also ameliorate severe depression through additional mechanisms involving astrocytes that are independent of the monoamine system to some extent.”
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- Authors
- Morioka, N., Suekama, K., Zhang, F. F., Kajitani, N., Hisaoka‐Nakashima, K., Takebayashi, M., & Nakata, Y.
- Affiliations
- Hiroshima University (JP)
- National Hospital Organization (JP)
- Corresponding author
- Morioka, N
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2014-05-15
- Volume
- 171
- Issue
- 11
- Pages
- 2854-2867
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC4243860
- OpenAlex
- W1505571651
- Cited by
- 73
- References
- 61
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 6 · 2017: 9 · 2016: 4 · 2015: 7 · 2014: 1
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Japan Society for the Promotion of Science (23591686, 24790253)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amitriptyline, connexin 43, gap junctional intercellular communication, cortical astrocytes, p38 MAPK, c-fos, tricyclic antidepressants, major depressive disorder, antidepressant mechanism, curcumin, tanshinone IIA, SB202190
- MeSH terms
- Amitriptyline, Animals, Antidepressive Agents, Tricyclic, Astrocytes, Cell Communication, Cells, Cultured, Up-Regulation, Proto-Oncogene Proteins c-fos, Rats, Wistar, Gap Junctions, Connexin 43, Transcription Factor AP-1, p38 Mitogen-Activated Protein Kinases
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