Neuron Glia Biology

Research Article

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’

Shiquen Zhanga1, Baoman Lia1a2, Ditte Lovatta3a4, Junnan Xua1, Dan Songa1a2, Steven A. Goldmana3, Maiken Nedergaarda4, Leif Hertza1 and Liang Penga1a2 c1

a1 Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China

a2 Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, P.R. China

a3 Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA

a4 Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA

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.

Correspondence:

c1 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: hkkid08@yahoo.com