Chronic SSRI stimulation of astrocytic 5-HT2B receptors change multiple gene expressions/editings and metabolism of glutamate, glucose and glycogen: a potential paradigm shift.

Leif Hertz,Douglas L Rothman,Liang Peng,Baoman Li

doi:10.3389/fnbeh.2015.00025

Abstract

It is firmly believed that the mechanism of action of SSRIs in major depression is to inhibit the serotonin transporter, SERT, and increase extracellular concentration of serotonin. However, this undisputed observation does not prove that SERT inhibition is the mechanism, let alone the only mechanism, by which SSRI’s exert their therapeutic effects. It has recently been demonstrated that 5-HT2B receptor stimulation is needed for the antidepressant effect of fluoxetine in vivo. The ability of all five currently used SSRIs to stimulate the 5-HT2B receptor equipotentially in cultured astrocytes has been known for several years, and increasing evidence has shown the importance of astrocytes and astrocyte-neuronal interactions for neuroplasticity and complex brain activity. This paper reviews acute and chronic effects of 5-HT2B receptor stimulation in cultured astrocytes and in astrocytes freshly isolated from brains of mice treated with fluoxetine for 14 days together with effects of anti-depressant therapy on turnover of glutamate and GABA and metabolism of glucose and glycogen. It is suggested that these events are causally related to the mechanism of action of SSRIs and of interest for development of newer antidepressant drugs.

Highlights

SERT, THE 5-HT2B RECEPTOR AND SSRISSRI TARGETS It is generally thought that the molecular mechanism of SSRIs is the long-known blockage of serotonin (5-HT) reuptake by its transporter SERT (Fuller and Wong, 1977; Wong and Bymaster, 1995)
SSRI effects exerted via the 5-HT2B receptor had previously been described in cultured neurons (Launay et al, 2006) and in cultured astrocytes (Kong et al, 2002), where they have been thoroughly studied (Li et al, 2008a, 2009; Zhang et al, 2010)
Given the dominant role ascribed to neurons in the mechanisms of SSRIs and other psychiatric drugs it may appear surprising that studies found the major chronic impact of SSRIs in the fluoxetine-treated mice to be on astrocytes

Summary

INTRODUCTION

SSRI TARGETS It is generally thought that the molecular mechanism of SSRIs is the long-known blockage of serotonin (5-HT) reuptake by its transporter SERT (Fuller and Wong, 1977; Wong and Bymaster, 1995). Growth factor release may link glial 5-HT2B binding to the longer-term cellular and behavioral changes induced by SSRI stimulation of receptor tyrosine kinases of the epidermal growth factor (EGF) receptor (EGFR) Such an effect of G proteincoupled receptors represents a transactivation process, a common mechanism in astrocytes (Daub et al, 1997; Peavy et al, 2001; Peng, 2004; Du et al, 2009). The Jope group found in whole brain that 5-HT2B stimulation or acute fluoxetine administration decreases the levels of phosphorylated GSK3 (Li et al, 2004; Polter et al, 2012) This response was blunted or absent in young mice (Beurel et al, 2012), consistent with astrocytic localization since astrocytes are mainly generated postnatally (Schousboe, 1971; Ge et al, 2012). Up Gurevich et al (2002), Englander et al (2005), Schmauss et al (2010) Unaltered Le Poul et al (2000), Johnson et al (2009) Up or Unaltered Anthony et al (2000), Le Poul et al (2000) Unaltered Johnson et al (2009)

OBJECTIVES

Findings

CONCLUSIONS