Sigma-1 Receptor Activation by Fluvoxamine Ameliorates ER Stress, Synaptic Dysfunction and Behavioral Deficits in a Ketamine Model of Schizophrenia.
Mariam K Ahmed, Kareem Abdou, Weam W Ibrahim, Ahmed F. Mohamed, Noha A El-Boghdady
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology July 25, 2025 DOI: 10.1007/s11481-025-10231-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Ketamine-induced rat model of schizophrenia |
| Interventions | Fluvoxamine NE100 hydrochloride |
| Dose | fluvoxamine 30 mg/kg/day, NE100 1 mg/kg/day |
| Duration | 5-day ketamine induction, 14-day treatment |
| Topics | Esketamine Ketamine |
| Keywords | Chaperones Er stress Misfolded proteins Psychiatric disorders schizophrenia Sigma-1 receptor fluvoxamine Cognitive abilities Social interaction Nmdar signaling |
| Citations | 5 |
| Key points | Fluvoxamine, acting via sigma-1 receptor activation, improved cognitive and social deficits, reduced ER stress, and exerted anti-inflammatory and anti-apoptotic effects in a ketamine-induced rat model of schizophrenia. |
Abstract
Endoplasmic reticulum (ER) stress and misfolded proteins accumulation are recognized as central factors in the development of psychiatric disorders. This study evaluated the potential therapeutic effect of fluvoxamine, a potent sigma-1 receptor agonist in alleviating protein misfolding and the subsequent ER stress in ketamine-induced model of schizophrenia. NE100 hydrochloride, a sigma-1 receptor blocker, was used to investigate the role of this receptor in fluvoxamine-mediated effects. Rat model of schizophrenia was induced by intraperitoneal administration of ketamine (30 mg/kg/day) for 5 consecutive days. Then, rats were treated with fluvoxamine (30 mg/kg/day, p.o), with or without NE100 (1 mg/kg/day, i.p), for 14 days. Fluvoxamine improved the learning abilities, cognitive flexibility, and sociability functions of ketamine-subjected rats as evidenced in Morris water maze and three-chamber social interaction tests. It mitigated ketamine-induced inhibition of nNOS/PSD-95/NMDAR signaling pathway, thus augmented the function of parvalbumin-GABAergic neurons as indicated by increasing the prefrontal cortical levels of parvalbumin and GAD67. Fluvoxamine also attenuated the prefrontal cortical production of unfolded protein response markers, namely, IRE-1, PERK, and ATF-6, highlighting its ability to alleviate ER stress. Further, it exerted anti-apoptotic and anti-inflammatory effects as shown by lowering Iba-1, tumor necrosis factor-α (TNF-α), Bax, and caspase-12 levels contrary to elevating Bcl-2. Additionally, it attenuated the histopathological alterations in prefrontal cortical neurons. Noteworthy, the co-administration of NE100 reduced the advantageous effects of fluvoxamine, indicating the involvement of sigma-1 receptor in mediating the observed antipsychotic effects. Thus, sigma-1-mediated signaling pathways could be therapeutic targets for preventing or slowing schizophrenia progression.