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New perspectives in the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders

Grant number: 17/24304-0
Support type:Research Projects - Thematic Grants
Duration: February 01, 2019 - January 31, 2024
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal researcher:Francisco Silveira Guimaraes
Grantee:Francisco Silveira Guimaraes
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Pesquisadores principais:
Elaine Aparecida Del Bel Belluz Guimarães ; Leonardo Resstel Barbosa Moraes ; Sâmia Regiane Lourenço Joca
Assoc. researchers:Alline Cristina de Campos ; Ana Carolina de Castro Issy Pereira ; Ana Luisa Bernardes Terzian ; Antonio Cardozo dos Santos ; Ariandra Guerini Sartim ; Claudia Maria de Castro Batista ; Cristina Aparecida Jark Stern ; Daniele Cristina de Aguiar ; Elaine Aparecida Del Bel Belluz Guimarães ; Fabricio de Araujo Moreira ; Fernanda Grecco Grano ; Fernando Morgan de Aguiar Correa ; Frederico Rogério Ferreira ; Glauce Crivelaro Do Nascimento ; Leandro José Bertoglio ; Mariza Bortolanza ; Maurício dos Santos Pereira ; Nilson Carlos Ferreira Junior ; Pedro Henrique Gobira Nunes ; Rúbia Maria Monteiro Weffort de Oliveira ; Sabrina Francesca de Souza Lisboa
Associated scholarship(s):22/00198-4 - Involvement of nitric oxide with the behavioural and molecular changes induced by exposure to an intense stressor: possible effect of cannabidiol, BP.PD
22/00197-8 - Involvement of the medial prefrontal cortex (mPFC) in the rapid and sustained effect of drugs in a model of depression resistant to conventional antidepressants: possible involvement of endocannabinoid modulation on the cortical glutamatergic system, BP.PD
21/12917-2 - New perspectives on the use of drugs that modify atypical neurotransmitters in the treatment of neuropsychiatric disorders, BP.TT
+ associated scholarships 20/02297-4 - Conditioned and unconditioned stimulus send at fixed or randomized intervals: possible behavioral differences for the expression and extinction of conditioned fear memory, BP.IC
20/04145-7 - Investigation of the possible involvement of adenosinergic receptors in the behavioral effects induced by cannabidiol in mice using different animal models, BP.IC
19/26351-0 - Evaluation of paclitaxel-induced cognitive deficits in a 4T-1 murine mammary carcinoma model and possible protective effect of concomitant cannabidiol treatment, BP.IC
19/24591-4 - Mechanisms of cannabidiol antipsychotics effects in schizophrenia model based in neurodevelopment variation, BP.DR
19/18846-0 - Role of the endocannabinoid system in orofacial muscular pain related to Parkinson's Disease, BP.IC
19/26810-5 - Extracellular vesicles as signals of the hippocampal neurogenic niche: participation in the behavioral effects of cannabinoid and antidepressant drugs, BP.PD
18/15896-3 - Participation of DNA methylation in rapid and sustained antidepressant-like effects induced by Cannabidiol and Ketamine, BP.PD
18/20433-2 - Neuroprotective and behavioral effects of the PPAR³ agonist pioglitazone in a neurodevelopmental model of schizophrenia, BP.PD
17/14207-7 - The action of cannabinoid drugs in L-dopa-induced dyskinesia: analysis of neuroinflammation and glutamate release in glial cells, BP.PD - associated scholarships


The need to develop new therapeutic targets for the treatment of neuropsychiatric disorders is a consensus in the scientific literature. Endocannabinoids (eCBs) and nitric oxide (NO) have been proposed as two of these possible targets. Studies from our group have disclosed the therapeutic potential of drugs that interfere with these two atypical neurotransmitters in anxiety, depressive, psychotic disorders, Parkinson's disease, aggressive behavior and neurodegeneration/neurotoxicity. Cannabidiol (CBD), a non-psychotomimetic phytocannabinoid, which, among other effects, can increase the levels of the eCB anandamide, is already undergoing clinical trials to test its efficacy in some of these disorders. However, several important questions still remain related to the therapeutic potential of these drugs in other specific disorders as well as to the mechanisms involved. In the last few years our studies have indicated new possibilities, including facilitation of adult hippocampal neurogenesis and autophagy and the possible involvement of neuroinflammatory/neuroimmune mechanisms. The present project aimed at continuing this research line, trying to investigate 1. Which is the involvement and mechanisms of the anti-inflammatory effects of CBD and drugs that modify the NO and eCB system in their potential therapeutic effects?; 2. Which other neuropsychiatric disorders could benefice from these drugs?; 3. In case of co-morbities such as metabolic syndrome and anxiety disorders, in which an inflammatory component is present, would these new therapies be effective?; 4. Which other intra-cellular pathways would be involved?; 5. Which is the specific eCB involvement in the modulation of rewarding and aversive responses?; 6. Which specific epigenetic mechanisms are involved with these effects? (AU)

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Scientific publications (27)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
HARTMANN, ALICE; LISBOA, SABRINA FRANCESCA; SONEGO, ANDREZA BUZOLIN; COUTINHO, DEBORA; GOMES, FELIPE VILLELA; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 94, . (16/14282-6, 10/17343-0, 17/24304-0, 11/22523-0, 17/19731-6)
BORTOLANZA, MARIZA; DO NASCIMENTO, GLAUCE C.; RAISMAN-VOZARI, RITA; DEL-BEL, ELAINE. Doxycycline and its derivative, COL-3, decrease dyskinesia induced by l-DOPA in hemiparkinsonian rats. British Journal of Pharmacology, v. 178, n. 13, . (14/25029-4, 17/24304-0)
GONZALEZ-LIZARRAGA, FLORENCIA L.; PLOPER, DIEGO; AVILA, CESAR L.; SOCIAS, SERGIO B.; DOS-SANTOS-PEREIRA, MAURICIO; MACHIN, BELEN; DEL-BEL, ELAINE; MICHEL, PATRICK PIERRE; PIETRASANTA, I, LIA; RAISMAN-VOZARI, RITA; et al. CMT-3 targets different alpha-synuclein aggregates mitigating their toxic and inflammogenic effects. SCIENTIFIC REPORTS, v. 10, n. 1, . (17/24304-0, 18/03482-0, 14/25029-4, 17/14207-7)
RIBEIRO, MELISSA A.; AGUIAR, RAFAEL P.; SCARANTE, FRANCIELE F.; FUSSE, EDUARDO J.; DE OLIVEIRA, RUBIA M. W.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C.. pontaneous Activity of CB2 Receptors Attenuates Stress-Induced Behavioral and Neuroplastic Deficits in Male Mic. FRONTIERS IN PHARMACOLOGY, v. 12, . (17/24304-0, 15/05551-0)
ULIANA, DANIELA L.; ANTERO, LEANDRO S.; BORGES-ASSIS, ANNA B.; ROSA, JESSICA; VILA-VERDE, CARLA; LISBOA, SABRINA F.; RESSTEL, LEONARDO B. M.. Differential modulation of the contextual conditioned emotional response by CB1 and TRPV1 receptors in the ventromedial prefrontal cortex: Possible involvement of NMDA/nitric oxide-related mechanisms. JOURNAL OF PSYCHOPHARMACOLOGY, v. 34, n. 9, . (17/24304-0, 17/14473-9)
HEIMANN, ANDREA S.; DALE, CAMILA S.; GUIMARAES, FRANCISCO S.; REIS, RICARDO A. M.; NAVON, AMI; SHMUELOV, MICHAL A.; RIOLI, VANESSA; GOMES, IVONE; DEVI, LAKSHMI L.; FERRO, EMER S.. Hemopressin as a breakthrough for the cannabinoid field. Neuropharmacology, v. 183, . (16/04000-3, 19/06982-6, 17/24304-0)
ZADOR, FERENC; JOCA, SAMIA; NAGY-GROCZ, GABOR; DVORACSKO, SZABOLCS; SZUCS, EDINA; TOMBOLY, CSABA; BENYHE, SANDOR; VECSEI, LASZLO. Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 11, . (17/24304-0)
DOS SANTOS PEREIRA, MAURICIO; ABREU, GABRIEL HENRIQUE DIAS; ROCCA, JEREMY; HAMADAT, SABAH; RAISMAN-VOZARI, RITA; MICHEL, PATRICK PIERRE; DEL BEL, ELAINE. Contributive Role of TNF-alpha to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson's Disease. FRONTIERS IN PHARMACOLOGY, v. 11, . (14/25029-4, 18/03482-0, 17/24304-0, 17/14207-7)
BATISTA, LUARA AUGUSTA; DE ARAUJO MOREIRA, FABRICIO; DE AGUIAR, DANIELE CRISTINA. Interactions between the nitrergic and the endocannabinoid system in rats exposed to the elevated T-maze. ACTA NEUROPSYCHIATRICA, v. 33, n. 4, p. 206-210, . (17/24304-0)
MEYER, ERIKA; BONATO, JESSICA MENDES; MORI, MARCO AURELIO; MATTOS, BIANCA ANDRETTO; GUIMARAES, FRANCISCO SILVEIRA; MILANI, HUMBERTO; DE CAMPOS, ALLINE CRISTINA; WEFFORT DE OLIVEIRA, RUBIA MARIA. Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity. Molecular Neurobiology, v. 58, n. 10, . (17/24304-0)
MACIEL, IZAQUE DE SOUSA; SALES, AMANDA J.; CASAROTTO, PLINIO C.; CASTREN, EERO; BIOJONE, CAROLINE; JOCA, SAMIA R. L.. Nitric Oxide Synthase inhibition counteracts the stress-induced DNA methyltransferase 3b expression in the hippocampus of rats. European Journal of Neuroscience, . (15/25067-6, 15/06271-1, 17/24304-0)
SARTIM, A. G.; MARQUES, J.; SILVEIRA, K. M.; GOBIRA, P. H.; GUIMARAES, F. S.; WEGENER, G.; JOCA, S. R.. Co-administration of cannabidiol and ketamine induces antidepressant-like effects devoid of hyperlocomotor side-effects. Neuropharmacology, v. 195, . (17/24304-0)
NASCIMENTO, GLAUCE CRIVELARO; DE PAULA, BRUNA BALBINO; FERRARI, DANIELE P.; IYOMASA, DANIELA MIZUSAKI; PEREIRA, YAMBA C. L.; PEDRAZZI, JOAO F.; BORTOLANZA, MARIZA; ISSY, ANA CAROLINA; MARDEGAN ISSA, JOAO PAULO; LEITE-PANISSI, CHRISTIE R. A.; et al. Upregulation of FosB/Delta FosB in limbic circuits after tooth exodontia-induced occlusal instability in an experimental model of unpredictable chronic stress. Brain Research Bulletin, v. 176, p. 142-150, . (17/24304-0, 18/05146-7, 14/25029-4, 15/03053-3)
ROPKE, JIVAGO; FERREIRA-VIEIRA, TALITA H.; IGLESIAS, LIA P.; ASTH, LAILA; RIBEIRO, FABIOLA M.; MOREIRA, FABRICIO A.. Protective role of endocannabinoid signaling in an animal model of haloperidol-induced tardive dyskinesia. Pharmacology Biochemistry and Behavior, v. 206, . (17/24304-0)
SILVEIRA, KENNIA M.; WEGENER, GREGERS; JOCA, SAMIA R. L.. Targeting 2-arachidonoylglycerol signalling in the neurobiology and treatment of depression. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 129, n. 1, p. 3-14, . (17/24304-0)
PEDRAZZI, JOAO F. C.; SALES, AMANDA J.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.; CRIPPA, JOSE A. S.; DEL BEL, ELAINE. annabidiol prevents disruptions in sensorimotor gating induced by psychotomimetic drugs that last for 24-h with probable involvement of epigenetic changes in the ventral striatu. PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, v. 111, . (14/25029-4, 15/06515-8, 17/24304-0)
CORTEZ, ISADORA L.; RODRIGUES DA SILVA, NAIELLY; GUIMARAES, FRANCISCO S.; GOMES, FELIPE V.. Are CB2 Receptors a New Target for Schizophrenia Treatment?. FRONTIERS IN PSYCHIATRY, v. 11, . (17/24304-0, 18/17597-3)
IGLESIAS, LIA P.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. TRPV1 blockers as potential new treatments for psychiatric disorders. Behavioural Pharmacology, v. 33, n. 1, p. 2-14, . (17/24304-0)
DA SILVA, NAIELLY RODRIGUES; GOMES, FELIPE VILLELA; SONEGO, ANDREZA BUZOLIN; DA SILVA, NICOLE RODRIGUES; GUIMARAES, FRANCISCO SILVEIRA. Cannabidiol attenuates behavioral changes in a rodent model of schizophrenia through 5-HT1A, but not CB1 and CB2 receptors. PHARMACOLOGICAL RESEARCH, v. 156, . (17/24304-0, 18/17597-3)
LOPES, JADNA B.; BASTOS, JULIANA R.; COSTA, RAYSSA B.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice. Psychopharmacology, . (17/24304-0)
RAYMUNDI, ANA MARIA; DA SILVA, THIAGO R.; ZAMPRONIO, ALEKSANDER R.; GUIMARAES, FRANCISCO S.; BERTOGLIO, LEANDRO J.; STERN, CRISTINA A. J.. A time-dependent contribution of hippocampal CB1, CB2 and PPAR gamma receptors to cannabidiol-induced disruption of fear memory consolidation. British Journal of Pharmacology, v. 177, n. 4, SI, . (17/24304-0)
GOBIRA, P. H.; RONCALHO, A. L.; SILVA, N. R.; SILOTE, G. P.; SALES, A. J.; JOCA, S. R.. Adolescent cannabinoid exposure modulates the vulnerability to cocaine-induced conditioned place preference and DNMT3a expression in the prefrontal cortex in Swiss mice. Psychopharmacology, v. 238, n. 11, . (17/19284-0, 17/24304-0)
SANTOS-LOBATO, BRUNO L.; BORTOLANZA, MARIZA; PINHEIRO, LUCAS CESAR; BATALHAO, MARCELO E.; PIMENTEL, ANGELA V.; CAPELLARI-CARNIO, EVELIN; DEL-BEL, ELAINE A.; TUMAS, VITOR. Levodopa-induced dyskinesias in Parkinson's disease increase cerebrospinal fluid nitric oxide metabolites' levels. JOURNAL OF NEURAL TRANSMISSION, v. 129, n. 1, . (17/24304-0, 12/17626-7)
ASTH, LAILA; IGLESIAS, LIA P.; BRIANIS, RAYSSA C.; MARCAL, ANNA P.; SOARES, NICIA P.; AGUIAR, DANIELE C.; MOREIRA, FABRICIO A.. Effects of the monoamine stabilizer, (-)-OSU6162, on cocaine-induced locomotion and conditioned place preference in mice. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 394, n. 6, . (17/24304-0)
SCARANTE, FRANCIELE F.; RIBEIRO, MELISSA A.; ALMEIDA-SANTOS, ANA F.; GUIMARAES, FRANCISCO S.; CAMPOS, ALLINE C.. Glial Cells and Their Contribution to the Mechanisms of Action of Cannabidiol in Neuropsychiatric Disorders. FRONTIERS IN PHARMACOLOGY, v. 11, . (19/25984-0, 19/09178-3, 17/24304-0)
MORI, MARCO AURELIO; MEYER, ERIKA; DA SILVA, FRANCIELLY F.; MILANI, HUMBERTO; GUIMARAES, FRANCISCO SILVEIRA; OLIVEIRA, RUBIA MARIA WEFFORT. Differential contribution of CB1, CB2, 5-HT1A, and PPAR-gamma receptors to cannabidiol effects on ischemia-induced emotional and cognitive impairments. European Journal of Neuroscience, v. 53, n. 6, . (17/24304-0)

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