title: Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice.
abstract: BACKGROUND
  The neuroprotective agent riluzole has antidepressant-like properties in humans, but its mechanisms of action are unclear. Despite the increasing utility of transgenic and knockout mice in addressing such issues, previous studies aimed at characterizing biochemical mechanisms have been conducted in rats.
  
  
  OBJECTIVE
  We sought to optimize an oral riluzole administration protocol with antidepressant-like consequences in C57BL/6 mice, a common background strain in genetically modified mice.
  
  
  METHODS
  Riluzole (6-60 μg/ml) was dissolved in tap water and replaced regular drinking water for up to 3 weeks; sensitivity to tail suspension, forced swimming, and the locomotor response to extinction training in a model of "incentive disengagement" were tested. Peripheral and central effects of long-term 60-μg/ml treatment were also evaluated.
  
  
  RESULTS
  Riluzole had dose-dependent antidepressant-like effects in the forced swim test, and like chronic fluoxetine, exerted antidepressant-like actions in an adaptation of the "incentive disengagement" model at the highest concentration tested. This 60-μg/ml concentration also restored hippocampal brain-derived neuroptrophic factor (BDNF) expression after chronic corticosteroid exposure and increased glutamate glial transporter 1 (GLT-1, or EAAT2) expression without significantly affecting baseline locomotor activity, thymus and adrenal gland weights, or blood serum corticosterone. The lowest 6-μg/ml concentration increased locomotor activity, potentially consistent with an anxiolytic-like effect.
  
  
  CONCLUSIONS
  Riluzole's therapeutic potential for treating mood disorders may involve GLT-1 and BDNF, and we suggest this protocol could be used to further characterize its precise long-term biochemical mechanisms of action in animal models of depression.
authors.affiliation: Department of Psychiatry, Division of Molecular Psychiatry, Yale University, New Haven, CT 06511, USA. shannon.l.gourley@emory.edu
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Gourley
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Espitia
authors.forename: Gerard
authors.initials: G
authors.lastname: Sanacora
authors.forename: Jane R
authors.initials: JR
authors.lastname: Taylor
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009042:Motivation; D019782:Riluzole / Q000008:administration & dosage*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; D019782:Riluzole