Sigma-1 Receptor Activation by Fluvoxamine Ameliorates ER Stress, Synaptic Dysfunction and Behavioral Deficits in a Ketamine Model of Schizophrenia.

Fluvoxamine, a sigma-1 receptor agonist, alleviated learning deficits, cognitive inflexibility, and social impairments in a rat model of schizophrenia induced by ketamine. It restored nNOS/PSD-95/NMDAR signaling, increased parvalbumin and GAD67 levels in the prefrontal cortex, and reduced markers of unfolded protein response (IRE-1, PERK, ATF-6), indicating relief from ER stress. Fluvoxamine also lowered inflammatory markers (Iba-1, TNF-α) and apoptotic markers (Bax, caspase-12) while increasing Bcl-2, and reduced neuronal damage. Co-administration of the sigma-1 receptor blocker NE100 diminished these effects, implicating sigma-1 receptor signaling as a therapeutic target for schizophrenia.

Study at a glance

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.