title: p38 MAP kinase activation does not stimulate serotonin transport in rat brain: Implications for sickness behaviour mechanisms.
abstract: OBJECTIVE
  Several studies suggested an association between dysregulation of immune mediators and behavioural, neuroendocrine and neurochemical features of depression. Available data showed that cytokines affect the serotonin transporter (SERT) activity through p38 MAP kinase (MAPK)-dependent mechanisms in some cell lines and mice neurons (Zhu et al., Neuropsychopharmacology, 2006; 31:2121-31). The aim of this study was to investigate the interaction of Interleukin-1β (IL-1β) or p38 MAPK with SERT activity in rat brain and cell lines.
  
  
  METHODS
  Synaptosomes or cells were treated with IL-1β or the p38 MAPK activator anisomycin at different concentrations and end-points and the modulation of SERT activity as Km and Vmax was evaluated.
  
  
  RESULTS
  Treatments with IL-1β or anisomycin did not affect serotonin uptake and p38 MAPK activation in rat synaptosomes, in contrast to reports in mice (Zhu et al., Neuropsychopharmacology, 2010; 35:2510-20). The same treatments activated p38 MAPK phosphorylation in HeLa cells used as positive controls. Similarly, no changes after anisomycin treatment could be detected in [(3)H]serotonin uptake rate in LLC-PK cells expressing human SERT, although phosphorylated p38 MAPK levels augmented significantly. Direct cytokine release in brain was induced by intracerebroventricular administration of bacterial lipopolysaccaride. Although pro-inflammatory cytokines, such as IL-1ß, IL6, and Tumor Necrosis Factor α, showed significant increases in brain cortex, modulation of SERT activity in term of Km and Vmax was not detected.
  
  
  CONCLUSIONS
  These results imply that the stimulation of serotonin uptake by cytokines may not be a unique and fundamental mechanism in the pathology of depression induced by altered immune response.
authors.affiliation: Neurosciences CEDD, GlaxoSmithKline Medicine Research Centre, Verona, Italy; Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Birmingham, UK.
authors.forename: Filippo
authors.initials: F
authors.lastname: Andreetta
authors.affiliation: Cellular and Molecular Neuropharmacology Research Group, Section of Neuropharmacology and Neurobiology, Clinical and Experimental Medicine, The Medical School, University of Birmingham, Birmingham, UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
authors.affiliation: Neurosciences CEDD, GlaxoSmithKline Medicine Research Centre, Verona, Italy.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Wren
authors.affiliation: Neurosciences CEDD, GlaxoSmithKline Medicine Research Centre, Verona, Italy. Electronic address: lucia.carboni4@unibo.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Carboni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D055809:Illness Behavior / Q000502:physiology*; D053583:Interleukin-1beta / Q000494:pharmacology; D016018:Least-Squares Analysis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D013574:Synaptosomes / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D016207:Cytokines; D053583:Interleukin-1beta; D012701:Serotonin; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases