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Acute Restraint Stress Causes Anxiety-Related Behaviors and Neuronal Degeneration in the Ca1 and Pfc, Which Are Blocked by Crocin and D-Ap5 Publisher Pubmed



Gerami SS ; Ebrahimighiri M ; Zarrindast MR ; Khakpai F
Authors

Source: Journal of Psychiatric Research Published:2026


Abstract

Crocin, a water-soluble carotenoid known for its therapeutic potential in anxiety disorders, exhibits a range of beneficial properties such as anti-inflammatory, neuroprotective, and anti-anxiety effects. Despite its documented efficacy, the precise mechanism behind its anxiolytic action remains incompletely understood. Given crocin's known interaction with NMDA receptors within the glutamatergic system—particularly in cognitive processes—this study aimed to investigate its interplay with NMDA receptor modulators in regulating anxiety-related behaviors in male mice under an acute restraint stress (ARS) model. Mice were implanted with guide cannulas for intracerebroventricular (i.c.v.) drug administration and subjected to 4 h of immobilization to induce ARS. Anxiety was assessed using the elevated plus maze (EPM), which revealed that stressed mice displayed increased anxiogenic behaviors, reflected by reduced percentages of open arm time (%OAT) and open arm entries (%OAE). Additionally, ARS led to a rise in dark cell count in hippocampal CA1 and prefrontal cortical regions. Administration of NMDA (0.5 μg/mouse, i.c.v.) intensified anxiety-like behavior, whereas both D-AP5 (an NMDA antagonist; 0.5 μg/mouse, i.c.v.) and crocin (50 mg/kg, intraperitoneal (i.p.)) attenuated it. A sub-effective dose of NMDA (0.25 μg/mouse) counteracted the anxiolytic effects of crocin across multiple doses, while a sub-threshold dose of D-AP5 (0.25 μg/mouse) enhanced crocin-induced anxiety reduction. Synergistic anxiolytic effects between crocin and D-AP5 were observed in both stressed and non-stressed mice. These findings strongly indicate that crocin modulates anxiety-related behavior, at least partially, via interaction with NMDA receptors. © 2026 Published by Elsevier Ltd.
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