Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways

Author(s)

Biagioni, Audrey Francisco ^{[1, 2, 3]} ; de Freitas, Renato Leonardo ^{[1, 2, 3]} ; da Silva, Juliana Almeida ^{[1, 2, 3]} ; de Oliveira, Rithiele Cristina ^{[1, 2]} ; de Oliveira, Ricardo ^{[1, 2]} ; Alves, Vani Maria ^[2] ; Coimbra, Norberto Cysne ^{[1, 2, 3]}

Affiliation

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Farmacol, NAP USP Neurobiol Emocoes NuPNE, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] FMRP USP, Dept Farmacol, Lab Neuroanat & Neuropsicobiol, BR-14049900 Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, INeC, BR-14040901 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: Neuropharmacology; v. 67, p. 379-394, APR 2013.
• Web of Science Citations: 29

Abstract

Decrease of gamma-aminobutyric acid (GABA)-mediated neurotransmission in the dorsomedial hypothalamus (DMH) evokes instinctive fear-like responses. The aim of the present study was to investigate the involvement of the serotonin (5-HT)- and norepinephrine-mediated pathways of the endogenous pain. inhibitory system, including the dorsal raphe nucleus (DRN) and the locus coeruleus (LC), in the defensive responses and antinociceptive processes triggered by the blockade of GABAergic receptors in the DMH. The intra-hypothalamic microinjection of the GABA(A) receptor antagonist bicuculline (40 ng/200 nL) elicited elaborate defensive behaviours interspersed with exploratory responses. This escape behaviour was followed by significantly increased pain thresholds, a phenomenon known as fear-induced antinociception. Furthermore, at 5 and 14 days after DRN serotonin-containing neurons were damaged using the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), the frequency and duration of alertness and escape behaviour evoked by the GABA(A) receptor blockade in the DMH decreased, as well as fear-induced antinociception. Pre-treatment with the non-selective 5-HT receptor antagonist methysergide, the 5-HT2A/2C receptor antagonist ketanserin and the 5-HT2A receptor selective antagonist R-96544 in the LC also decreased fear-induced antinociception, without significant changes in the expression of defensive behaviours. These data suggest that the serotonergic neurons of the DRN are directly involved in the organisation of defensive responses as well as in the elaboration of the innate fear-induced antinociception. However, serotonin-mediated inputs from the NDR to the LC modulate only fear-induced antinociception and not the defensive behaviours evoked by GABA(A) receptor blockade in the DMH. (C) 2012 Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 09/02458-9 - Neuropharmacological study of the interaction between cannabinoid and opioid circuits of the substantia nigra, pars reticulata, on the activity of the nigrotectal GABAergic pathways, and of its role in the modulation of the innate fear-induced analgesia
• Grantee: Juliana Almeida da Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 08/08955-1 - Involvement of the Dorsal Raphe Nucleus Neural Networks and Serotonergic Neurotransmittion in the Locus Coeruleus in Antinociceptive Processess Induced by Oriented Escape Reaction Evoked by Chemical Stimulation of the Medial Hypothalamus.
• Grantee: Audrey Franceschi Biagioni
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 07/01174-1 - Study of the Involvement of opioid-, serotonergic- and noradrenergic-mechanisms of the pain endogenous inhibitory system in antinociceptive processes induced by oriented escape reactions evoked by chemical stimulation of the merdial hypothalamus
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/54014-7 - Acquisition of a biophotonic imaging system and a multiphoton microscopy system for in vivo imaging
• Grantee: Enilza Maria Espreafico
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 12/03798-0 - Involvement of opioid and endocanabinoid receptors of the substantia nigra on the activity of Nigro-Tectal GABAergic pathways during defensive behaviour elicited by rodents confronted with venomous snakes
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 09/17258-5 - Study of the involvement of nitrergic system and of glutamatergic and cannabinoid-mediated neurotransmission from the medial prefrontal cortex in the analgesia induced by elaborated escape reactions evoked by GABAergic blockade in the medial hypothalamus
• Grantee: Renato Leonardo de Freitas
• Support Opportunities: Scholarships in Brazil - Post-Doctoral