title: 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.
abstract: The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH.
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
authors.forename: Audrey Franceschi
authors.initials: AF
authors.lastname: Biagioni
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
authors.forename: Rithiele Cristina
authors.initials: RC
authors.lastname: de Oliveira
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil; Mato Grosso Federal University Medical School (UFMT), Av. Alexandre Ferronato, 1200, Reserva 35, Setor Industrial, 78550-000 Sinop, Mato Grosso, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: de Oliveira
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
authors.forename: Juliana Almeida
authors.initials: JA
authors.lastname: da Silva
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
authors.forename: Tayllon
authors.initials: T
authors.lastname: dos Anjos-Garcia
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
authors.forename: Camila Marroni
authors.initials: CM
authors.lastname: Roncon
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Alexandre Pinto
authors.initials: AP
authors.lastname: Corrado
authors.affiliation: Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Laboratory of Neuropsychopharmacology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Hélio
authors.initials: H
authors.lastname: Zangrossi
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil; NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil. Electronic address: ncoimbr@fmrp.usp.br.
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000704:Analysis of Variance; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism*; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D003911:Dextrans; D058787:GABA-A Receptor Antagonists; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; C076397:biotinylated dextran amine; D044282:Receptor, Serotonin, 5-HT1A; D001710:Biotin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D001640:Bicuculline
keywords: 5-HT(1A) receptor; Antinociception; Biotinylated dextran amine neurotracer; Dorsal raphe nucleus outputs; Dorsomedial hypothalamus; Panic-like behaviour