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

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Abstract

Rationale

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.

Objectives

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.

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Acknowledgments

The authors thank Drs. Mounira Banasr and Mary Torregrossa for advice and feedback.

Conflicts of interest

Dr. Sanacora has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Evotec, Eli Lilly & Co., Johnson & Johnson, Roche, Novartis, and Sepracor Inc. He has also received additional grant support from AstraZeneca, Bristol-Myers Squibb, Merck & Co., Roche, and Sepracor Inc. In addition, he is a co-inventor on a filed patent application by Yale University (PCTWO06108055A1) concerning the use of glutamate-modulating drugs as antidepressants and anxiolytics.

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Authors and Affiliations

  1. Department of Psychiatry, Division of Molecular Psychiatry, Yale University, New Haven, CT, 06511, USA

    Shannon L. Gourley, Jonathan W. Espitia, Gerard Sanacora & Jane R. Taylor

  2. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA

    Shannon L. Gourley

  3. Department of Psychology, Yale University, New Haven, CT, 06520, USA

    Jane R. Taylor

  4. Interdepartmental Neuroscience Program, Yale University, New Haven, CT, 06520, USA

    Jane R. Taylor

  5. Department of Pediatrics, Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA, 30329, USA

    Shannon L. Gourley

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  1. Shannon L. Gourley
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  2. Jonathan W. Espitia
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  4. Jane R. Taylor
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Corresponding author

Correspondence to Shannon L. Gourley.

Additional information

This work was supported by NIH MH079680 (SLG), NIH MH081211 (GS), the Interdisciplinary Research Consortium on Stress, Self-control and Addiction [UL1-DE19586 and the NIH Roadmap for Medical Research/Common Fund, AA017537 (JRT)], and the Connecticut Department of Mental Health and Addiction Services (JRT, GS).

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Gourley, S.L., Espitia, J.W., Sanacora, G. et al. Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice. Psychopharmacology 219, 805–814 (2012). https://doi.org/10.1007/s00213-011-2403-4

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