Vortioxetine improved negative and cognitive symptoms of schizophrenia in subchronic MK-801 model in rats

Abstract

Schizophrenia is a devastating psychiatric disorder with complex symptoms and neurobiology. Serotonergic dysregulation is known to contribute to the pathogenesis of schizophrenia although dopaminergic and glutamatergic systems are thought to have central roles in neurobiology. No significant success can be achieved in the treatment of negative and cognitive symptoms while positive symptoms can be significantly reduced with current pharmacotherapy. Vortioxetine is a new multimodal antidepressant with 5-HT1A agonism, 5-HT1B partial agonism, 5-HT3, 5-HT7, and 5-HT1D antagonism, and serotonin reuptake inhibition. A limited number of studies suggest its therapeutic effect on the negative and cognitive symptoms of schizophrenia. Therefore, we investigated the potential beneficial effects of vortioxetine on behavioral and molecular deficits in the MK-801 model of schizophrenia in rats. Female Wistar albino rats (10-12 weeks) were grouped as saline, MK-801 (0.2 mg/kg), MK-801 + vortioxetine (2.5 mg/kg), MK-801 + vortioxetine (5 mg/kg), MK-801 + vortioxetine (10 mg/kg), MK-801 + risperidone (0.3 mg/kg), MK-801 + haloperidol (1 mg/kg) (n = 8 in each group). MK-801 has been daily administered (i.p.) for 14 days. Vortioxetine and antipsychotic treatments were injected for 21 days after a washout period of MK-801 and locomotor activity (LA), social interaction (SI), novel object recognition (NOR), Y-maze and prepulse inhibition (PPI) tests were performed at the 16-20th days of treatments, respectively. ELISA test was conducted to evaluate molecular analyses. MK-801 decreased PPI (%), social behaviors, and discrimination index in NOR and alternation (%) in the Y-maze test. In NOR and Y-maze tests, especially vortioxetine 5 and 10 mg/kg increased discrimination index and alternation (%) compared to MK-801. In addition, vortioxetine administration increased social behaviors. Moreover, MK-801 decreased GAD67 and parvalbumin levels while vortioxetine increased these protein levels compared to MK-801. Herein, we first suggested a potential therapeutic effect of vortioxetine, a new multimodal antidepressant, on negative and cognitive symptoms and neurobiological deficits including GAD67 and parvalbumin low expression in the MK-801 model in rats. It would be beneficial to confirm our results in different rodent models and to shed light on the possible mechanisms underlying these effects.

Keywords: GAD67; Novel object recognition test; Parvalbumin; Schizophrenia; Social interaction test; Vortioxetine.