¹Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: X Li, Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Ave South, Sparks Center 1075, Birmingham, AL 35294-0017, USA. Tel: +1 205 934 1169; Fax: +1 205 934 3709; E-mail: xili@uab.edu

Received 22 December 2003; Revised 28 January 2004; Accepted 9 February 2004; Published online 24 March 2004.

Abstract

The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3 (GSK3) in mouse brain in vivo. GSK3 is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3 were 300–400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3 levels. This indicates that serotonergic regulation of the phosphorylation of GSK3 is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3 and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3 may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.