title: 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.
abstract: Decrease of γ-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-HT(2A/2C) receptor antagonist ketanserin and the 5-HT(2A) 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.
authors.affiliation: Laboratório de Neuroanatomia & Neuropsicobiologia, Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (FMRP-USP), Av. dos Bandeirantes 3900, Ribeirão Preto, SP 14049-900, Brazil.
authors.forename: Audrey Francisco
authors.initials: AF
authors.lastname: Biagioni
authors.forename: Renato Leonardo
authors.initials: RL
authors.lastname: de Freitas
authors.forename: Juliana Almeida
authors.initials: JA
authors.lastname: da Silva
authors.forename: Rithiele Cristina
authors.initials: RC
authors.lastname: de Oliveira
authors.forename: Ricardo
authors.initials: R
authors.lastname: de Oliveira
authors.forename: Vani Maria
authors.initials: VM
authors.lastname: Alves
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D000818:Animals; D004302:Dorsomedial Hypothalamic Nucleus / Q000502:physiology*; D005239:Fear / Q000502:physiology* / Q000523:psychology; D008125:Locus Coeruleus / Q000502:physiology*; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D010147:Pain Measurement / Q000379:methods*; D011903:Raphe Nuclei / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D059326:Serotonergic Neurons / Q000502:physiology*