title: Elevation of cortical serotonin transporter activity upon peripheral immune challenge is regulated independently of p38 mitogen-activated protein kinase activation and transporter phosphorylation.
abstract: The serotonin transporter (SERT) is responsible for high-affinity serotonin (5-HT) uptake from extracellular fluid and is a prominent pharmacological target in the treatment of depression. In recent years, depression has also been linked to immune system activation. Inflammatory conditions can cause sickness behaviour and depression-like symptoms in both animals and humans. Since SERT has been proposed as one of the molecular targets in inflammation-induced depression, we applied the widely used lipopolysaccharides (LPS) model to study the effects of peripheral inflammation on SERT activity in the brain. We show that 24 h after intraperitoneal LPS administration, SERT-mediated 5-HT uptake is significantly enhanced in the frontal cortex. Analysis of uptake kinetics revealed that the transport capacity (Vmax ) of cortical SERT was increased in LPS-injected animals, while the Km value remained unchanged. The increase in Vmax was neither due to increased SERT protein expression nor increased synaptic surface exposure. The suppression of SERT activity upon inhibition of p38 MAPK was not selective for LPS-induced enhancement of SERT function. In addition, SERT activity changes in LPS-treated rats are unaffected by nitric oxide synthase and protein kinase G inhibitors. Using the Phos-Tag method, we identified five SERT-specific protein bands representing distinct phosphorylation states of SERT. However, the enhancement of SERT activity in LPS-treated rats was not correlated with altered transporter phosphorylation. Together with previous studies by others, our results suggest that SERT is regulated by multiple mechanisms in response to peripheral immune system activation. Peripheral injection of lipopolysaccharide (LPS) induces characteristic sickness and depression-like behaviour in rats over a period of at least 24 h. We show here that the activity of the serotonin transporter (SERT), a prominent antidepressant target, is up-regulated 24 h following LPS administration. In contrast to previous studies focusing on earlier responses to LPS treatment, we found that SERT function is selectively enhanced in the frontal cortex, independently of the p38 MAPK pathway. Our study provides further insight into molecular mechanisms underlying inflammation-induced depression.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwamborn
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Eric
authors.initials: E
authors.lastname: Brown
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.
authors.forename: Jana
authors.identifier: http://orcid.org/0000-0002-5949-8355
authors.initials: J
authors.lastname: Haase
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005106:Exploratory Behavior; D007249:Inflammation / Q000139:chemically induced* / Q000276:immunology / Q000523:psychology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; C482440:Sert1 protein, rat; D012701:Serotonin; D019001:Nitric Oxide Synthase; D017869:Cyclic GMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Phos-Tag; lipopolysaccharide; p38 mitogen-activated protein kinase; serotonin transporter; sickness behaviour