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5-HT2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional ‘serotonin-specific reuptake inhibitors’

Published online by Cambridge University Press:  16 September 2010

Shiquen Zhang ,
Baoman Li ,
Ditte Lovatt ,
Junnan Xu ,
Dan Song ,
Steven A. Goldman ,
Maiken Nedergaard ,
Leif Hertz  and
Liang Peng
Shiquen Zhang
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China
Baoman Li
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China
Ditte Lovatt
Affiliation:
Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA
Junnan Xu
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China
Dan Song
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China
Steven A. Goldman
Affiliation:
Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
Maiken Nedergaard
Affiliation:
Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA
Leif Hertz
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China
Liang Peng*
Affiliation:
Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China
*
Correspondence should be addressed to: Liang Peng, College of Basic Medical Sciences, China Medical University, No. 92 Beier Road, Heping District, Shenyang, P.R. China phone: 86(24)23256666-5130 email: [email protected]
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Abstract

In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the ‘serotonin-specific reuptake inhibitor’ (SSRI) fluoxetine leads acutely to 5-HT2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) with an EC50 of ~5 μM, and chronically to ERK1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A2 (cPLA2) with ten-fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK1/2 and mRNA and protein expression of cPLA2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT2 receptor, the 5-HT2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA2a expression during chronic treatment; citalopram had a similar effect at 0.1–0.5 μM; these are therapeutically relevant concentrations.

Keywords

CitalopramcPLA2ERKfluorescence-activated cell sortingparoxetine
Type
Research Article
Information
Neuron Glia Biology , Volume 6 , Issue 2 , May 2010 , pp. 113 - 125
Copyright
Copyright © Cambridge University Press 2010

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