Amitriptyline up‐regulates connexin43‐gap junction in rat cultured cortical astrocytes via activation of the p38 and c‐Fos/AP‐1 signalling pathway

• Published in: British journal of pharmacology Vol. 171; no. 11; pp. 2854 - 2867
• Main Authors: Morioka, N, Suekama, K, Zhang, F F, Kajitani, N, Hisaoka‐Nakashima, K, Takebayashi, M, Nakata, Y
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2014; BlackWell Publishing Ltd
• Subjects: amitriptyline; Amitriptyline - pharmacology; Animals; Antidepressants; Antidepressive Agents, Tricyclic - pharmacology; AP‐1; astrocyte; Astrocytes - drug effects; Astrocytes - physiology; Cell Communication - drug effects; Cells, Cultured; Communication; Connexin 43 - metabolism; connexin43; gap junction; Gap Junctions - drug effects; Gap Junctions - physiology; major depressive disorder; p38; p38 Mitogen-Activated Protein Kinases - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Rats, Wistar; Research Papers; Transcription Factor AP-1 - metabolism; Up-Regulation; amitriptyline; connexin43; major depressive disorder; p38; antidepressants; gap junction; AP-1; astrocyte
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12614

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 Cx43 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 Cx43 and gap junction intercellular communication (GJIC) in rat primary cultured cortical astrocytes was investigated. We also investigated the role of p38 MAPK intracellular signalling pathway in the amitriptyline‐induced expression of Cx43 and GJIC.
Key Results
Treatment with amitriptyline for 48 h significantly up‐regulated Cx43 mRNA, protein and GJIC. The up‐regulation of Cx43 was not monoamine‐related since noradrenaline, 5‐HT and dopamine did not induce Cx43 expression and pretreatment with α‐ and β‐adrenoceptor antagonists had no effect. Intracellular signalling involved p38 MAPK, as amitriptyline significantly increased p38 MAPK phosphorylation and Cx43 expression and GJIC were significantly blocked by the p38 inhibitor SB 202190. Furthermore, amitriptyline‐induced Cx43 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 p38 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.