Avaliação da participação da via das quinureninas e do receptores NMDA no efeito do tipo-antidepressivo da vilazodona no teste de suspensão pela cauda em camundongos

Abstract

Vilazodone (VZD) is an antidepressant that selectively inhibits the reuptake of serotonin (5- HT), in addition to being a partial agonist of the 5-HT1A receptor. Several studies in recent years have shown the involvement of the glutamatergic system in the etiology of depression. The data found in the investigation of this system suggest a reduction in N-methyl-Daspartate (NMDA) receptor activity with the consequent activation of intracellular signaling pathways related to the inhibition of these receptors are reported, suggesting the potential of this approach for the treatment of depression. In addition, it has observed the role of the metabolites of the kynurenine pathway in depression, since they demonstrated that the disproportion of the neuroprotective effects of kynurenic acid (NMDA receptor antagonist) and the neurotoxic effects of quinolinic acid (QA), being an agonist of the receptor NMDA and 3-hydroxykynurenine (3-HK) implicate the kynurenine pathway in the pathophysiology of depression. In view of the participation of the kynurenine pathway and NMDA receptors in the pathogenesis of depression and the importance of these molecular targets for the effectiveness of antidepressants, the present study investigated the antidepressant potential of VZD in mice, using the predictive animal model for assessing antidepressant activity, the tail suspension test (TST). Additionally, the animals were also submitted to the open-field test to rule out the possibility that the effect found in the TST is related to alterations in locomotor activity. Acute administration of VZD produced an antidepressant-like effect at a dose of 3 mg / kg, reducing the immobility time in the TST. To evaluate the mechanism of action involved in the effect found, the participation of the kynurenine pathway and the NMDA receptor was investigated. Thus, treatment with kynurenine pathway metabolites such as Lkynurenine (L-KYN), 3-HK and QA at effective doses of 1.7 mg / kg i.p., 10 mg / kg, i.p. and 3 nmol / site, i.c.v., produced a depressive-like effect, significantly increasing the immobility time in the TST. The anti-immobility effect of VZD at the effective dose (3 mg / kg, i.p.) was not prevented by pretreating sub-effective doses of L-KYN (0.83 mg / kg, i.p.), 3-HK (3 , 33 mg / kg, i.p.) and QA (1 nmol / site, i.c.v.). In addition, administration of a sub-effective dose of VZD (0.3 mg / kg, i.p.) produced an antidepressant-like effect on TST when combined with a sub-effective dose of ketamine (1 mg / kg, i.p.). In both tests, there was no change in the locomotor activity of the animals. Our data demonstrate that VZD exerted an antidepressantlike effect on TST and that antidepressant effect appears to involve inhibition of NMDA receptors.