Activation of the TRKB receptor mediates the panicolytic-like effect of the NOS inhibitor aminoguanidine

Deidiane Elisa Ribeiro,Plinio Cabrera Casarotto,Ailton Jr Spiacci,Gabriel Gripp Fernandes,Lucas César Pinheiro,José Eduardo Tanus-Santos,Hélio Jr Zangrossi,Francisco Silveira Guimarães,Samia Regiane Lourenço Joca,Caroline Biojone

doi:10.1016/j.pnpbp.2019.04.007

Abstract

Nitric oxide (NO) triggers escape reactions in the dorsal periaqueductal gray matter (dPAG), a core structure mediating panic-associated response, and decreases the release of BDNF in vitro. BDNF mediates the panicolytic effect induced by antidepressant drugs and produces these effects per se when injected into the dPAG. Based on these findings, we hypothesize that nitric oxide synthase (NOS) inhibitors would have panicolytic properties associated with increased BDNF signaling in the dPAG. We observed that the repeated (7 days), but not acute (1 day), systemic administration of the NOS inhibitor aminoguanidine (AMG; 15 mg/kg/day) increased the latency to escape from the open arm of the elevated T-maze (ETM) and inhibited the number of jumps in hypoxia-induced escape reaction in rats, suggesting a panicolytic-like effect. Repeated, but not acute, AMG administration (15 mg/kg) also decreased nitrite levels and increased TRKB phosphorylation at residues Y706/7 in the dPAG. Notwithstanding the lack of AMG effect on total BDNF levels in this structure, the microinjection of the TRK antagonist K252a into the dPAG blocked the anti-escape effect of this drug in the ETM. Taken together our data suggest that the inhibition of NO production by AMG increases the levels of pTRKB, which is required for the panicolytic-like effect observed.

Highlights

The periaqueductal gray matter (PAG) is a midbrain structure critically associated with the expression of escape/flight responses
The present study investigated the effect of the non-selective Nitric oxide (NO) synthase inhibitor AMG on the escape response of rats submitted to the elevated T maze (ETM) and hypoxia tests, and the involvement of tropomyosin-related kinase B receptors (TRKB) signaling in the AMG-induced effects
Due to the higher basal expression of nNOS compared to iNOS (Vincent and Kimura, 1992; Onstott et al, 1993), especially in the dorsal PAG (dPAG), it is very unlikely that in our experimental conditions AMG is acting significantly upon iNOS

Summary

Introduction

The periaqueductal gray matter (PAG) is a midbrain structure critically associated with the expression of escape/flight responses. Chemical or electrical stimulation of the dorsal regions of the PAG (dorsolateral and dorsomedial columns) in animals triggers escape reactions that have been associated with panic attacks (Depaulis et al, 1992; Brandão et al, 2008). The neuronal nitric oxide synthase (NOS1 or nNOS) enzyme is highly expressed in the PAG, especially in its dorsolateral columns (Vincent and Kimura, 1992; Onstott et al, 1993). Activation of the NMDA receptor (NMDAr) by glutamate stimulates NO synthesis through calcium influx (Garthwaite et al, 1989), resulting in a positive-feedback response. Injections of NO donors or NMDAreceptor agonists into the dPAG precipitates escape reactions, while local administration of NOS inhibitors or NMDAr antagonists prevents such behaviors (De Oliveira et al, 2001; Miguel and Nunes-de-Souza, 2006; Aguiar and Guimarães, 2009)

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