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The Journal of Neuroscience, April 11, 2007, 27(15):4201-4209; doi:10.1523/JNEUROSCI.3110-06.2007
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Behavioral/Systems/Cognitive
Biochemical and Behavioral Evidence for Antidepressant-Like Effects of 5-HT6 Receptor Stimulation
Per Svenningsson,1,2 * Eleni T. Tzavara,3,4 * Hongshi Qi,2 Robert Carruthers,1 Jeffrey M. Witkin,3 George G. Nomikos,3 andPaul Greengard1 1Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, 2Department of Physiology and Pharmacology, Karolinska Institute, 171 77 Stockholm, Sweden, 3Eli Lilly and Company, Lilly Corporate Center, Neuroscience Discovery Research, Indianapolis, Indiana 46285, and 4Institut National de la Santé et de la Recherche Médicale U-513, 94010 Créteil, France
Correspondence should be addressed to either of the following: Dr. Paul Greengard, Laboratory of Molecular and Cellular Neuroscience, 1230 York Avenue, The Rockefeller University, New York, NY 10021, Email: greengd{at}mail.rockefeller.edu; or Dr. Per Svenningsson, Department of Physiology and Pharmacology, Nanna Svartz väg 2, Karolinska Institute, 171 77 Stockholm, Sweden, Email: per.svenningsson{at}ki.se
The primary action of several antidepressant treatments used in the clinic raises extracellular concentrations of serotonin (5-HT), which subsequently act on multiple 5-HT receptors. The present study examined whether 5-HT6 receptors might be involved in the antidepressant-like effects mediated by enhanced neurotransmission at 5-HT synapses. A selective 5-HT6 receptor antagonist, SB271046, was evaluated for its ability to counteract fluoxetine-induced biochemical and behavioral responses in mice. In addition, biochemical and behavioral effects of the 5-HT6 receptor agonist, 2-ethyl-5-methoxy-N,N-dimethyltryptamine (EMDT), were assessed in mice to ascertain whether enhancement of 5-HT6 receptor-mediated neurotransmission engenders antidepressant-like effects. SB271046 significantly counteracted the stimulatory actions of fluoxetine on cortical c-fos mRNA, phospho-Ser845-GluR1, and in the tail suspension antidepressant assay, whereas it had no effect on these parameters by itself. EMDT increased the phosphorylation states of Thr34-DARPP-32 and Ser845-GluR1, both in brain slices and in the intact brain, which were effects also seen with the antidepressant fluoxetine; as with fluoxetine, these effects were demonstrated to be independent of D1 receptor stimulation. Systemic administration of EMDT increased c-fos mRNA expression in the striatum and cerebral cortex and reduced immobility in the tail suspension test. The antidepressant-like effects of EMDT in the tail suspension test were prevented by SB271046. Our results indicate that 5-HT6 receptor stimulation may be a mechanism initiating some of the biochemical and behavioral outcomes of 5-HT reuptake inhibitors, such as fluoxetine. These findings also indicate that selective 5-HT6 receptor agonists may represent a novel antidepressant drug class.
Key words: serotonin; antidepressants; fluoxetine; signal transduction; protein phosphorylation; tail suspension test
Received July 21, 2006; revised March 4, 2007; accepted March 6, 2007.
Correspondence should be addressed to either of the following: Dr. Paul Greengard, Laboratory of Molecular and Cellular Neuroscience, 1230 York Avenue, The Rockefeller University, New York, NY 10021, Email: greengd{at}mail.rockefeller.edu; or Dr. Per Svenningsson, Department of Physiology and Pharmacology, Nanna Svartz väg 2, Karolinska Institute, 171 77 Stockholm, Sweden, Email: per.svenningsson{at}ki.se
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