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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 and Paul 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

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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

This article has been cited by other articles:

				J. L. Warner-Schmidt, M. Flajolet, A. Maller, E. Y. Chen, H. Qi, P. Svenningsson, and P. Greengard Role of p11 in Cellular and Behavioral Effects of 5-HT4 Receptor Stimulation J. Neurosci., February 11, 2009; 29(6): 1937 - 1946. [Abstract] [Full Text] [PDF]

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