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Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

By Yashika Bansal, Corey Fee, Keith Misquitta, Sierra Anna-Maria Codeluppi, Etienne Sibille, Robert Berman, Vladimir Coric, Gerard Sanacora, Mounira Banasr

Posted 07 Aug 2020
bioRxiv DOI: 10.1101/2020.08.07.242057

Background: Chronic stress-related illnesses, such as major depressive disorder and post-traumatic stress disorder share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs, which do not directly target Glu signaling, fail to provide adequate benefit for many patients and are associated with high relapse rates. Riluzole modulates glutamatergic neurotransmission by increasing metabolic cycling and modulating signal transduction. Clinical studies exploring riluzole efficacy in stress-related disorders have provided varied results. However, the utility of riluzole for treating specific symptom dimensions or as a prophylactic treatment has not been comprehensively assessed. Methods: We investigated whether chronic prophylactic riluzole (~12-15/kg/day p.o.) could prevent the emergence of behavioural deficits induced by unpredictable chronic mild stress (UCMS) in mice. We assessed: i) anxiety-like behaviour using the elevated-plus maze, open field test, and novelty-suppressed feeding, ii) mixed anxiety/anhedonia-like behaviour in the novelty-induced hypophagia test and, iii) anhedonia-like behaviour using the sucrose consumption test. Z-scoring summarized changes across tests measuring similar dimensions. In a separate learned helplessness (LH) cohort, we investigated whether chronic prophylactic riluzole treatment could block the development of helplessness-like behaviour. Results: UCMS induced an elevation in anxiety-, anhedonia-like behaviour, and overall behavioural emotionality that was blocked by prophylactic riluzole. In the LH cohort, prophylactic riluzole blocked the development of helplessness-like behaviour. Conclusion: This study supports the utility of riluzole as a prophylactic medication for preventing anhedonia, anxiety, and helplessness symptoms associated with stress-related disorders.

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