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

Abstract

BackgroundChronic stress-related illnesses, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs (ADs), 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’s 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.MethodsWe investigated whether chronic prophylactic riluzole (∼12-15/kg/day p.o.) could prevent the emergence of behavioral deficits induced by unpredictable chronic mild stress (UCMS) in mice. We assessed i) anxiety-like behavior using the elevated-plus maze, open field test, and novelty-suppressed feeding, ii) mixed anxiety/anhedonia-like behavior in the novelty-induced hypophagia test and, iii) anhedonia-like behavior using the sucrose consumption test. Z-scoring summarized changes across tests measuring similar outcomes. In a separate learned helplessness (LH) cohort, we investigated whether chronic preventative riluzole treatment could block the development of helplessness-like behavior.ResultsUCMS induced an elevation in anxiety-, anhedonia-like behavior, and overall behavioral emotionality that was blocked by prophylactic riluzole. In the LH cohort, preventative riluzole blocked the development of helplessness-like behavior.ConclusionThis study supports the utility of riluzole as a prophylactic medication, and potential relapse-preventing treatment targeting anhedonia, anxiety, and helplessness symptoms associated with stress-related disorders.Significance StatementRiluzole is a glutamate-modulating drug with mixed evidence of efficacy in clinical studies of patients with stress-related disorders. Based on evidence suggesting that glutamatergic dysfunction contributes to the pathogenesis of stress-related disorders, we investigated whether prophylactic treatment with riluzole could prevent the onset of behavioral deficits induced by unpredictable chronic mild stress or learned helplessness in mice. Riluzole effectively prevented the emergence of anxiety-, anhedonia-like behavior, and overall behavioral emotionality in mice exposed to unpredictable chronic mild stress. In a separate cohort, riluzole blocked the emergence of helplessness-like behavior as measured in an active avoidance paradigm. These results support testing riluzole as a prophylactic treatment strategy in stress-related illnesses such as major depressive disorder or post-traumatic stress disorder.

Riluzole prevents stress-induced spine plasticity in the hippocampus but mimics it in the amygdala

“…Riluzole has been used as a neuroprotective agent for treating amyotrophic lateral sclerosis (ALS) patients ( Lacomblez et al, 1996 ), and has also been reported to have antidepressant effects ( Brennan et al, 2010 ; Pittenger et al, 2008 ; Sanacora et al, 2007 ). Moreover, of relevance to the present study, chronic riluzole treatment reversed chronic stress/corticosterone-induced behavioral deficits along with GLT-1 expression, glutamate metabolism and brain derived neurotropic factor (BDNF) in the hippocampus and the prefrontal cortex of rodents ( Banasr et al, 2010 ; Bansal et al, 2021 ; Gourley et al, 2012 ). However, little is known about the effects of riluzole, with or without stress, on neuronal and astrocytic morphology in the rodent hippocampus and amygdala.…”

“…Apart from its effects on glutamate levels in and around the synapse, the use of riluzole is also relevant from a therapeutic perspective. A growing body of research, in both humans and pre-clinical rodent models, points to the potential use of riluzole as an antidepressant ( Banasr et al, 2010 ; Bansal et al, 2021 ; Brennan et al, 2010 ; Gourley et al, 2012 ; Pittenger et al, 2008 ; Sanacora et al, 2007 ; Spangler et al, 2020 ). As depression-like symptoms are often precipitated by some form of stress, animal models of stress have been used extensively to investigate cellular mechanisms of depression.…”

Prefrontal Cortex Astroglia Modulate Anhedonia-like Behavior

“…The NSF, NIH, EPM, OF, FST and LM activity tests were performed as in (34,(37)(38)(39). For the stress study, the 1-hour sucrose consumption test, PhenoTyper Test, LM activity, and coat state (CS) were performed as in (20,(34)(35)(36).…”

“…For the stress study, the 1-hour sucrose consumption test, PhenoTyper Test, LM activity, and coat state (CS) were performed as in (20,(34)(35)(36). Anxiety and anhedonia z-scores were calculated as in (34,37). See supplementary methods section.…”

Prophylactic Efficacy of Riluzole against Anxiety- and Depressive-Like Behaviors in Two Rodent Stress Models

“…Further inquiries can be directed to the corresponding author (M.B.). A preprint version of this article is available on BioRxiv modified on December 22, 2022 [132] .…”