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Regulation of Signal Transduction Pathways and Gene Expression by Mood Stabilizers and Antidepressants

From the Department of Psychiatry and Behavioral Neurosciences (G.C., K.A.H., J.M.B., G.J.M., D.G., H.K.M.), Pharmacology (H.K.M.), Radiology (G.J.M.), and Cellular and Clinical Neurobiology Program (G.C., G.J.M., H.K.M.), Wayne State University School of Medicine, Detroit, MI.

Address reprint requests to: Husseini K. Manji, MD, FRCPC, Director, Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, UHC 9B, 4201 St. Antoine Blvd., Detroit, MI 48201. Email: hmanji{at}med.wayne.edu

OBJECTIVE: To determine whether the currently available evidence supports the hypothesis that antidepressants and mood stabilizers may bring about some of their long-term therapeutic effects by regulating signal transduction pathways and gene expression in the central nervous system.

METHODS: To address this question, we reviewed the evidence showing that chronic administration of antidepressants and mood stabilizers involves alterations in signaling pathways and gene expression in the central nervous system.

RESULTS: A large body of data has shown that lithium and valproate exert effects on the protein kinase C signaling pathway and the activator protein 1 family of transcription factors; in contrast, antidepressants affect the cyclic adenosine monophospate pathway and may bring about their therapeutic effects by modulating cyclic adenosine monophosphate–regulated gene expression in the central nervous system.

CONCLUSIONS: Given the key roles of these signaling cascades in the amplification and integration of signals in the central nervous system, the findings have clear implications not only for research into the etiology and pathophysiology of the severe mood disorders but also for the development of novel and innovative treatment strategies.

Key Words: mood disorders • protein kinase C • gene expression • lithium • antidepressants • valproate.

Abbreviations: AC = adenylate cyclase; ADP = adenosine diphosphate; AP-1 = activator protein 1; cAMP = cyclic adenosinemonophosphate; CNS = central nervous system; CREB = cAMPresponse element–binding protein; DAG = diacylglycerol; DMI= desipramine; GAP-43 = growth-associated protein 43; GDP =guanosine diphosphate; GSK-3 = glycogen synthase kinase 3; GTP = guanosine triphosphate; IP3 = inositol1,4,5-trisphosphate; MARCKS = myristoylated alanine-rich C kinasesubstrate; PI = phosphatidylinositol; PIP₂ =phosphotidylinositol-4,5-bisphosphate; PKC = protein kinaseC; PLC = phospholipase C; RGS = regulator of G proteinsignaling; TPA = 12-o-tetradecanoyl-phorbol13-acetate; ßAR = ß-adrenergic; 5HT = serotonin.

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