Astrocytes as a 5-HT2B-Mediated SERT-Independent SSRI Target, Slowly Altering Depression-Associated Genes and Function

Author(s): Leif Hertz, Baoman Li, Dan Song, Jienan Ren, Lu Dong, Ye Chen, Liang Peng.

Journal Name: Current Signal Transduction Therapy

Volume 7 , Issue 1 , 2012

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Abstract:

When fluoxetine, the first of the presently used serotonin-specific reuptake inhibitors (SSRIs), was approved in 1987, two effects of the drug had been established: inhibition of serotonin reuptake by the serotonin transporter (SERT), and partial displacement of serotonin binding to cultured astrocytes, which have no SERT expression. At that time astrocytes were generally assumed to be unimportant for brain function. Accordingly, inhibition of SERT has since been regarded as the mechanism responsible for SSRIs effects in spite of several problems: the delay in therapeutic activity, although the inhibition of serotonin uptake is immediate; lack of quantitative correlation between potency of inhibition by different SSRIs and their therapeutic plasma levels (even considering protein binding); and 80% SERT occupancy at minimum-effective doses. Moreover, little information has been obtained about the molecular mechanisms alleviating major depression and obsessive-compulsive disorder (OCD). In 1987 the 5-HT2B receptor was unknown, but it is now established to have the highest affinity between 5-HT receptors for SSRIs, with especially high affinity during chronic treatment. Here we summarize data from cultured mouse astrocytes and astrocytes obtained from the brains of fluoxetinetreated mice, supporting the role of the astrocytic binding: only small differences in affinity for the 5-HT2B receptor between different SSRIs; a week-long-delayed upregulation of the phospholipase, cPLA2a, and the kainate receptor GluK2, with simultaneous increased editing of the latter, reducing its possible stimulation of neuronal glutamatergic signaling. These effects are genetically and functionally correlated with major depression and OCD, including the therapeutic potential of drugs inhibiting glutamatergic activity.

Keywords: astrocyte-to neuron signaling, calcium, gene editing, glutamate receptor GluK2, phospholipase cPLA2, serotonin specific reuptake inhibiotr, major depression, SERT, fluoxetine, OCD

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Article Details

VOLUME: 7
ISSUE: 1
Year: 2012
Page: [65 - 80]
Pages: 16
DOI: 10.2174/1574362799278154

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