, Volume 219, Issue 3, pp 805–814 | Cite as

Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice

  • Shannon L. Gourley
  • Jonathan W. Espitia
  • Gerard Sanacora
  • Jane R. Taylor
Original Investigation



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.


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.


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.


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.


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.


Riluzole Depression Glutamate Antidepressant Incentive BDNF Extinction GLT-1 EATT2 Extinction 


  1. Adachi M, Barrot M, Autry AE, Theobald D, Monteggia LM (2008) Selective loss of brain-derived neurotrophic factor in the dentate gyrus attenuates antidepressant efficacy. Biol Psychiatry 63:642–629CrossRefGoogle Scholar
  2. Autry AE, Grillo CA, Piroli GG, Rothstein JD, McEwen BS, Reagan LP (2006) Glucocorticoid reulgation of GLT-1 glutamate transporter isoform expression in rat hippocampus. Neuroendocrinology 83:371–379PubMedCrossRefGoogle Scholar
  3. Azbill RD, Mu X, Springer JE (2000) Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 871:175–180PubMedCrossRefGoogle Scholar
  4. Banasr M, Duman RS (2007) Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. CNS Neurol Disord Drug Targets 6:311–320PubMedCrossRefGoogle Scholar
  5. Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psych 64:863–870CrossRefGoogle Scholar
  6. Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL, Sanacora G (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psych 15:501–511CrossRefGoogle Scholar
  7. Caldarone BJ, Karthigeyan K, Harrist A, Hunsberger JG, Witmack E, King SL et al (2003) Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice. Psychopharmacology (Berl) 170:94–101CrossRefGoogle Scholar
  8. Conti AC, Cryan JF, Dalvi A, Lucki I, Blendy JA (2002) cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 22:3262–3268PubMedGoogle Scholar
  9. Coric V, Milanovic S, Wasylink S, Patel P, Malison R, Krystal JH (2003) Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology 167:219–220PubMedGoogle Scholar
  10. Crowley JJ, Blendy JA, Lucki I (2005) Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test. Psychopharmacology 183:257–264PubMedCrossRefGoogle Scholar
  11. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493PubMedCrossRefGoogle Scholar
  12. Duman RS, Heninger GR, Nestler EJ (1997) A molecular and cellular theory of depression. Arch Gen Psychiatry 54:597–606PubMedCrossRefGoogle Scholar
  13. Ferguson GA (1978) Statistical analysis in psychology and education. McGraw Hill, New YorkGoogle Scholar
  14. Frizzo ME, Dall'Onder LP, Dalcin KB, Souza DO (2004) Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol 24:123–128PubMedCrossRefGoogle Scholar
  15. Fumagalli E, Bigini P, Barbera S, De Paola M, Mennini T (2006) Riluzole, unlike the AMPA antagonist RPR119990, reduces motor impairment and partially prevents motoneuron death in the wobbler mouse, a model of neurodegenerative disease. Exp Neurol 198:114–128PubMedCrossRefGoogle Scholar
  16. Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T (2008) Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol 578:171–176PubMedCrossRefGoogle Scholar
  17. Gourley SL, Taylor JR (2009) Regulation and reversal of a persistent depression-like syndrome in rodent. Current Protocols in Neuroscience, Chapter 9, Unit 9.32Google Scholar
  18. Gourley SL, Wu FJ, Kiraly DD, Ploski JE, Kedves AT, Duman RS, Taylor JR (2008a) Regionally specific regulation of ERK MAP kinase in a model of antidepressant-sensitive chronic depression. Biol Psychiatry 63:353–359PubMedCrossRefGoogle Scholar
  19. Gourley SL, Kiraly DD, Howell JL, Olausson P, Taylor JR (2008b) Acute hippocampal BDNF restores motivational and forced swim performance after corticosterone. Biol Psychiatry 64:884–890PubMedCrossRefGoogle Scholar
  20. Gourley SL, Wu FJ, Taylor JR (2008c) Corticosterone regulates pERK1/2 in a chronic depression model. Ann N Y Acad Sci 1148:509–514PubMedCrossRefGoogle Scholar
  21. Gourley SL, Kedves AT, Olausson P, Taylor JR (2009) A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 34:707–716PubMedCrossRefGoogle Scholar
  22. Groves JO (2007) Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry 12:1079–1088PubMedCrossRefGoogle Scholar
  23. Holmes PV (2003) Rodent models of depression: reexamining validity without anthropomorphic inference. Crit Rev Neurobiol 15:143–174PubMedCrossRefGoogle Scholar
  24. Katoh-Semba R, Asano T, Euda H, Morishita R, Takeuchi IK, Inaguma Y, Kato K (2002) Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J 16:1328–1330PubMedGoogle Scholar
  25. Klinger E, Barta SG, Kemble ED (1974) Cyclic activity changes during extinction in rats: a potential animal model of depression. Animal Learn Mem 2:313–316CrossRefGoogle Scholar
  26. Lowy MT, Gault L, Yamamoto BK (1993) Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus. J Neurochem 61:1957–1960PubMedCrossRefGoogle Scholar
  27. Lowy MT, Wittenberg L, Yamamoto BK (1995) Effects of acute stress on hippocampal glutamate levels and spectrin proteolysis in young and aged rats. J Neurochem 65:268–274PubMedCrossRefGoogle Scholar
  28. Mathew SJ, Keegan K, Smith L (2005) Glutamate modulators as novel interventions for mood disorders. Rev Bras Psiquiatr 27:243–248PubMedCrossRefGoogle Scholar
  29. Mathew SJ, Murrough JW, aan het Rot M, Collins KA, Reich DL, Charney DS (2010) Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial. Int J Neuropyschopharmacol 13:71–82CrossRefGoogle Scholar
  30. Mayorga AJ, Lucki I (2001) Limitations on the use of the C57BL/6 mouse in the tail suspension test. Psychopharmacology 155:110–112PubMedCrossRefGoogle Scholar
  31. Mineur YS, Picciotto MR, Sanacora G (2007) Antidepressant-like effects of ceftriaxone in male C57BL/6 J mice. Biol Psych 61:250–252CrossRefGoogle Scholar
  32. Mirza NR, Bright JL, Stanhope KJ, Wyatt A, Harrington NR (2005) Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels? Psychopharmacology 180:159–168PubMedCrossRefGoogle Scholar
  33. Munro G, Erichsen HK, Mirza NR (2007) Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety. Neuropsychopharmacology 53:609–618Google Scholar
  34. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  35. O'Neil MF, Moore NA (2003) Animal models of depression: are there any? Hum Psychopharmacol 18:239–254PubMedCrossRefGoogle Scholar
  36. Pekary AE, Sattin A, Blood J, Furst S (2008) TRH and TRH-like peptide expression in rat following episodic or continuous corticosterone. Psychoneuroendocrinology 2008:1183–1197CrossRefGoogle Scholar
  37. Pittenger C, Coric V, Banasr M, Bloch M, Krystal JH, Sanacora G (2008) Riluzole in the treatment of mood and anxiety disorders. CNS Drugs 22:761–786PubMedCrossRefGoogle Scholar
  38. Porsolt R, Le Pichon M, Jalfe M (1977) Depression: a new animal model sensitive to antidepressant treatment. Nature 266:730–732PubMedCrossRefGoogle Scholar
  39. Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 6:219–233PubMedCrossRefGoogle Scholar
  40. Reagan LP, Rosell DR, Wood GE, Spedding M, Muñoz C, Rothstein J, McEwen BS (2004) Chronic restraint stress up-regulates GLT-1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc Natl Acad Sci USA 101:2179–2184PubMedCrossRefGoogle Scholar
  41. Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433:73–77PubMedCrossRefGoogle Scholar
  42. Sanacora G, Kendell SF, Fenton L, Coric V, Krystal JH (2004) Riluzole augmentation for treatment-resistant depression. Am J Psychiatry 161:2132PubMedCrossRefGoogle Scholar
  43. Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, Krystal JH (2007) Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry 61:822–825PubMedCrossRefGoogle Scholar
  44. Shirayama Y, Chen AC-H, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261PubMedGoogle Scholar
  45. Singh J, Zarate CA, Krystal AD (2004) Case report: successful riluzole augmentation therapy in treatment-resistant bipolar depression following the development of rash with lamotrigine. Psychopharmacology 173:227–228PubMedCrossRefGoogle Scholar
  46. Sung B, Lim G, Mao J (2003) Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 23:2899–2910PubMedGoogle Scholar
  47. Taliaz D, Stall N, Dar DE, Zangen A (2010) Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis. Mol Psychiatry 15:80–92PubMedCrossRefGoogle Scholar
  48. Willner P (1984) The validity of animal models of depression. Psychopharmacology 83:1–16PubMedCrossRefGoogle Scholar
  49. Wood GE, Young LT, Reagan LP, Chen B, McEwen BS (2004) Stress-induced structural remodeling in hippocampus: prevention by lithium treatment. Proc Natl Acad Sci 101:3973–3978PubMedCrossRefGoogle Scholar
  50. Yang CH, Huang CC, Hsu KS (2005) Behavioral stress enhances hippocampal CA1 long-term depression through the blockade of the glutamate uptake. J Neurosci 25:4288–4293PubMedCrossRefGoogle Scholar
  51. Zarate CA, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK (2004) An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 161:171–174PubMedCrossRefGoogle Scholar
  52. Zarate CA, Quiroz JA, Singh JB, Denicoff KD, De Jesus G, Luckenbaugh DA, Charney DS, Manji HK (2005) An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 57:430–432PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Shannon L. Gourley
    • 1
    • 2
    • 5
  • Jonathan W. Espitia
    • 1
  • Gerard Sanacora
    • 1
  • Jane R. Taylor
    • 1
    • 3
    • 4
  1. 1.Department of Psychiatry, Division of Molecular PsychiatryYale UniversityNew HavenUSA
  2. 2.Department of Molecular Biophysics and BiochemistryYale UniversityNew HavenUSA
  3. 3.Department of PsychologyYale UniversityNew HavenUSA
  4. 4.Interdepartmental Neuroscience ProgramYale UniversityNew HavenUSA
  5. 5.Department of Pediatrics, Yerkes National Primate Research CenterEmory UniversityAtlantaUSA

Personalised recommendations