Lithium Increases Tyrosine Hydroxylase Levels Both In Vivo and In Vitro

Abstract

Lithium, a simple monovalent cation, is the mainstay in the treatment of manic-depressive illness, but despite extensive research, its mechanism of action remains to be elucidated. Because lithium requires chronic administration for therapeutic efficacy and because its beneficial effects last well beyond its discontinuation, it has been postulated that lithium may exert major effects at the genomic level. We have previously shown that lithium, at therapeutically relevant concentrations, increases gene expression through the activator protein-i (AP-1) transcription factor pathway in vitro. In the present study, we have sought to determine if lithium also increases the expression of endogenous genes known to be regulated by AP-1 and have therefore investigated the effects of lithium on tyrosine hydroxylase (TH) levels. Male Wistar rats were treated with LiCI for 9 days (subacute) or 4 weeks (chronic), and TH levels were measured in frontal cortex, hippocampus, and striatum using immunoblotting. Chronic (but not subacute) lithium treatment resulted in significant increases in TH levels in rat frontal cortex, hippocampus, and striatum. Lithium (1 mM) also increased TH levels in human SH-SY5Y neuroblastoma cells in vitro, indicating that lithium increases TH levels in both rodent and human tissues, likely via a direct cellular effect. These effects are compatible with (but likely not exclusively due to) an effect on the DNA binding of the 12-O-tetradecanoylphorbol 13-acetateresponse element to the AP-1 family of transcription factors. Key Words: Lithium-Activator protein-i -Tyrosine hydroxylase-Glycogen synthase kinase-3-Manic-depressive illness. J. Neurochem. 70, 1768Neurochem. 70, -1771Neurochem. 70, (1998.Manic-depressive illness (MDI) is a common (lifetime prevalence of 1.5%), severe, chronic, and life-threatening disease (Goodwin and Jarnison, 1990). The discovery of lithium' s efficacy as a mood-stabilizing agent revolutionized the treatment of patients with MDI (Goodwin and Jamison, 1990;Schou, 1991). Despite extensive research, however, the biochemical basis for lithium's antimanic and moodstabilizing actions remains to be fully elucidated . In recent years, it has become increasingly appreciated that any relevant biochemical model proposed for the effects of many psychotropic drugs (including mood stabilizers, antidepressants, and antipsychotics) must attempt to account for their special temporal clinical profile-in particular, that the therapeutic effects require a lag period for onset of action and are generally not immediately reversed on discontinuation Hyman and Nestler, 1996). Patterns of effects requiring such prolonged administration of the drug suggest alterations at the genomic level Hyman and Nestler, 1996). In this context, it is noteworthy that we recently found that valproate (another drug with long-term efficacy in the treatment of MDI) and lithium both produced a time-and concentrationdependent increase in the DNA binding of the 12-O-tetradecanoylphorbol 13-acetate response eleme...

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“…Presented in part at the 37th annual meeting of the American College of Neuropsychopharmacology, Dec. [14][15][16][17][18] 1998 The authors thank Lisa Roach, Stephanie Ley, the nuclear medicine technologists (Michelle Early, John Macmullan, Andrea Perez, Gary Wisinewski) and the radiochemistry staff (Ronald Baldwin and Lou Amici) for their assistance with this study.…”

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