title: Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience.
abstract: The prelimbic medial prefrontal cortex (PL) is an important encephalic structure involved in the expression of emotional states. In a previous study, intra-PL injection of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, reduced the expression of fear conditioning response. Although its mechanism remains unclear, CBD can facilitate 5HT1A receptor-mediated neurotransmission when injected into several brain structures. This study was aimed at verifying if intra-PL CBD could also induce anxiolytic-like effect in a conceptually distinct animal model, the elevated plus maze (EPM). We also verified if CBD effects in the EPM and contextual fear conditioning test (CFC) depend on 5HT1A receptors and previous stressful experience. CBD induced opposite effects in the CFC and EPM, being anxiolytic and anxiogenic, respectively. Both responses were prevented by WAY100,635, a 5HT1A receptor antagonist. In animals that had been previously (24h) submitted to a stressful event (2h-restraint) CBD caused an anxiolytic, rather than anxiogenic, effect in the EPM. This anxiolytic response was abolished by previous injection of metyrapone, a glucocorticoid synthesis blocker. Moreover, restraint stress increased 5HT1A receptors expression in the dorsal raphe nucleus, an effect that was attenuated by injection of metyrapone before the restraint procedure. Taken together, these results suggest that CBD modulation of anxiety in the PL depend on 5HT1A-mediated neurotransmission and previous stressful experience.
authors: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Instituto de Neurociências e Comportamento (INeC), University of São Paulo, Ribeirão Preto, Brazil. Electronic address: manoelafogaca@usp.br.
authors: M V
authors: MV
authors: Fogaça
authors: Psychology Department, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Brazil; Instituto de Neurociências e Comportamento (INeC), University of São Paulo, Ribeirão Preto, Brazil.
authors: F M C V
authors: FM
authors: Reis
authors: Instituto de Neurociências e Comportamento (INeC), University of São Paulo, Ribeirão Preto, Brazil; Group of Neuroimmunology, Laboratory of Immunopharmacology, Institute of Biological Sciences and School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Infectious Diseases and Tropical Medicine Program, Medical School, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors: A C
authors: AC
authors: Campos
authors: Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
authors: F S
authors: FS
authors: Guimarães
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D002185:Cannabidiol / Q000008:administration & dosage / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008797:Metyrapone / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000503:physiopathology; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012149:Restraint, Physical; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D014151:Anti-Anxiety Agents; D004791:Enzyme Inhibitors; D010879:Piperazines; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D008797:Metyrapone
keywords: 5HT(1A) receptors; Anxiety; Cannabidiol; Glucocorticoids; Prefrontal cortex; Stress