title: Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon.
abstract: Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways.
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 14049-900, São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto 14050-220, São Paulo, 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 14049-900, São Paulo, Brazil.
authors.forename: Audrey Francisco
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 14049-900, São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto 14050-220, São Paulo, Brazil.
authors.forename: Rafael Carvalho
authors.initials: RC
authors.lastname: Almada
authors.affiliation: Department of Neurosciences and Behavioural Sciences, Division of Psychiatry, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto 14049-900, São Paulo, Brazil.
authors.forename: José Alexandre
authors.initials: JA
authors.lastname: de Souza Crippa
authors.affiliation: Department of Neurosciences and Behavioural Sciences, Division of Psychiatry, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto 14049-900, São Paulo, Brazil.
authors.forename: Jaime Eduardo
authors.initials: JE
authors.lastname: Cecílio Hallak
authors.affiliation: Department of Neurosciences and Behavioural Sciences, Division of Psychiatry, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto 14049-900, São Paulo, Brazil.
authors.forename: Antônio Waldo
authors.initials: AW
authors.lastname: Zuardi
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 14049-900, São Paulo, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto 14050-220, São Paulo, Brazil; Neurobiology of Emotions Research Centre (NAP-USP-NuPNE), Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, São Paulo, Brazil. Electronic address: ncoimbr@fmrp.usp.br.
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology*; D002185:Cannabidiol / Q000008:administration & dosage / Q000494:pharmacology*; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D008845:Microinjections; D010147:Pain Measurement / Q000187:drug effects; D010200:Panic / Q000187:drug effects* / Q000502:physiology; D065841:Pars Reticulata / Q000187:drug effects*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013477:Superior Colliculi / Q000187:drug effects*
chemical_list: D000700:Analgesics; D043884:Receptor, Cannabinoid, CB1; D002185:Cannabidiol; D001640:Bicuculline
keywords: CB(1)-cannabinoid receptor-signalled mechanisms; GABA(A) receptor; Innate fear-induced antinociception; Panic attack-like behaviour; Striatum-nigral disinhibitory/nigro-tectal inhibitory GABAergic pathways; Superior colliculus