Typical and atypical neurotransmitters in neuropsychiatric disorders

• Grant number: 07/03685-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: December 01, 2008
• End date: November 30, 2012
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Francisco Silveira Guimaraes
• Grantee: Francisco Silveira Guimaraes
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: Antonio Waldo Zuardi ; Elaine Aparecida Del Bel Belluz Guimarães ; Fernando Morgan de Aguiar Correa ; Frederico Guilherme Graeff
• Associated researchers: Antonio de Padua Carobrez ; Cristina Marta Del-Ben ; Hélio Zangrossi Júnior ; Jaime Eduardo Cecilio Hallak ; José Alexandre de Souza Crippa ; Leandro José Bertoglio ; Leonardo Resstel Barbosa Moraes ; Mario Francisco Pereira Juruena ; Rodrigo Fiacadori Tavares ; Rúbia Maria Monteiro Weffort de Oliveira ; Sâmia Regiane Lourenço Joca
• Associated research grant(s): 12/50896-8 - Cannabidiol regulation of fear memory processing and associated brain function, AP.R
• Associated scholarship(s): 12/00390-0 - Study of envolviment of endocanabinoid system in the medial pre-frontal cortex of rats on the modulation of autonomic responses during restraint stress: possibile interection with glutamatergic and nitrergic systems, BP.DR; 12/02143-0 - CANNABIDIOL EFFECTS IN PREDICTIVE MODELS FOR ANTIPSYCHOTIC ACTION, BP.MS; 11/19801-8 - Mechanisms involved in the behavioral and pro-neurogenic effects of repeated administration of cannabidiol in mice submitted to chronic unpredictable stress, BP.DR; + associated scholarships 11/11449-3 - Signaling pathways and brain structures involved in Nitric Oxide/Dopamine interaction of Sensorimotor gating, BP.PD; 11/02746-4 - Involvement of endocannabinoid system modulating repetitive behavior: possible participation of brain-derived neurotrophic factor (BDNF), BP.PD; 11/01849-4 - Effects of cannabidiol administration into the ventral medial prefrontal cortex of rats submitted to an animal model of depression, BP.MS; 11/08990-4 - Typical and atypical neurotransmitters in neuropsychiatric disorders, BP.TT; 09/12856-1 - Investigation of the glutamatergic and dopaminergic systems modulation by the nitrergic system on the sensorimotor gating processing: possible implications to schizophrenia, BP.MS; 10/17343-0 - Evaluation of CBD effects on the molecular and behavioral changes induced by repeated treatment with MK-801, BP.DR; 10/09462-9 - Study of peripheral mechanisms involved in the cardiovascular response during sepsis in rats: possible involvement of the endocannabinoid system, BP.PD; 10/07286-9 - Involvement of corticotropin-releasing factor (CRF)in dorsal periaqueductal grey in modulation of defensive behaviours related to anxiety and panic disorders., BP.DR; 10/07544-8 - Involvement of the pathway prefrontal cortex - dorsal raphe nucleus - dorsal periaqueductal gray in the regulation of defensive responses associated to the anxiety and to the panic, BP.DR; 09/11220-6 - Evaluation of the role of molecular targets in the neurobiology of depressive disorder using interference RNA, BP.PD; 09/08181-9 - Basal ganglia neuroplasticity: role of nitric oxide on Parkinsons Disease and L-Dopa-induced dyskinesias, BP.DR; 09/00323-9 - Study of the involvement of hippocampal nNOS/sGC pathway on stress-induced behavioral consequences., BP.IC; 08/10267-6 - Evaluation of the BDNF role on the antidepressant-like effects produced by inhibition of the nitric oxide production, BP.DR; 08/03123-8 - Role of 5-HT1A and 5-HT2A serotoninergic receptors of the dorsomedial nucleus of the hypothalamus in the mediation of defensive behaviors related to panic, BP.PD; 08/03177-0 - "Involvement of TRPV1 receptors and glutamtergic and nitrergic neurons located in the dorsolateral periaquedcutal grey on defensive reactions in rats", BP.PD; 07/06999-9 - Study of possible interaction between cannabinoid and nitrergic systems in the dorsolateral periaqueductal gray on modulation of defensive behaviors in rats, BP.DR; 07/06555-3 - Effects of antipanic drugs on BDNF expression in the rat dorsal periaqueductal gray matter, BP.DR; 07/07070-3 - Effects of cannabidiol on behavioral and plastic consequences promoted by stress, BP.DR; 07/04863-2 - Involvement of glutmatergic/nitrergic neurotransmission in prosencephalic and mesencephalic structures on the modulation of the conditioned emotional response in rats, BP.PD; 07/05084-7 - Glucocorticoid Receptor (GR) and Mineralocorticoid Receptor (MR) function, associate to psychoneuroendocrine and psychometric assessment as outcome predictor in depressive patients, BP.PD - associated scholarships

Abstract

Several pieces of evidence, including those originated from our group in Ribeirão Preto in the last 30 years, indicate that typical (glutamate, GABA and serotonin) and atypical (nitric oxide, NO) neurotransmitters are involved in anxiety, mood, psychotic and related motor disorders. More recently the endocannabinoid system was also related to these disorders. The main goal of the present project is to extend these observations, studying possible brain mechanisms of these behavioral changes. In addition, we will also investigate other factors such as hormones (cortisol and oxitocine) and cannabidiol that can also modify those systems. To achieve this goal a multidisciplinary approach will be employed that will include well established behavioral techniques for experiments in animals, healthy volunteers and patients, as well as the more recent approaches of brain image and molecular biology. The project will contribute to the following specific problems: 1. role of typical (serotonin, glutamate) and atypical (NO, cannabinoids) neurotransmitters on behavioral responses to aversive stimuli such as predator exposure or animals models of anxiety (predator odor exposure, elevated plus or T mazes, Vogel conflict test, conditioned emotional response) in specific brain regions (medial prefrontal cortex, amygdaloid complex, hippocampal formation, premammilary nucleus of the hypothalamus, dorsolateral periaqueductal gray, raphe nuclei and cuneiform nucleus); 2. role of atypical neurotransmitters in behavioral, cardiovascular and hippocampal gene expression changes induced by stress; 3. Role of NO in modulation of basal ganglia dopaminergic neurotransmission and sensory-motor gating; 4. Clinical effects of interference on serotonin- or GABA-mediated neurotransmission in human anxiety model and emotional processing; 5. Effects of hormonal interference on serotonin-mediated neurotransmission in human responses to aversive events; 6. Role of NO- and glutamate-mediated neurotransmission in psychosis; 7. Effects of cannabidiol in animal models of anxiety and depression and in bipolar patients. (AU)

Scientific publications

(28)

(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)

GOMES, FELIPE V.; REIS, DANIEL G.; ALVES, FERNANDO H. F.; CORREA, FERNANDO M. A.; GUIMARAES, FRANCISCO S.; RESSTEL, LEONARDO B. M.. Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. JOURNAL OF PSYCHOPHARMACOLOGY, v. 26, n. 1, SI, p. 104-113, JAN 2012. (07/03685-3)

GOMES DE OLIVEIRA, DANIELLE CHAVES; CHAGAS, MARCOS HORTES N.; GARCIA, LUIS VICENTE; CRIPPA, JOSE ALEXANDRE S.; ZUARDI, ANTONIO W.. Oxytocin interference in the effects induced by inhalation of 7.5% CO2 in healthy volunteers. HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL, v. 27, n. 4, p. 378-385, JUL 2012. (07/03685-3)

DEL-BEN, CRISTINA M.; FERREIRA, CESAR A. Q.; SANCHEZ, TIAGO A.; ALVES-NETO, WOLME C.; GUAPO, VINICIUS G.; DE ARAUJO, DRAULIO B.; GRAEFF, FREDERICO G.. Effects of diazepam on BOLD activation during the processing of aversive faces. JOURNAL OF PSYCHOPHARMACOLOGY, v. 26, n. 4, p. 443-451, APR 2012. (07/03685-3)

STERN, C. A. J.; DO MONTE, F. H. M.; GAZARINI, L.; CAROBREZ, A. P.; BERTOGLIO, L. J.. ACTIVITY IN PRELIMBIC CORTEX IS REQUIRED FOR ADJUSTING THE ANXIETY RESPONSE LEVEL DURING THE ELEVATED PLUS-MAZE RETEST. Neuroscience, v. 170, n. 1, p. 214-222, SEP 29 2010. (07/03685-3)

GRANJEIRO, ERICA M.; GOMES, FELIPE V.; GUIMARAES, FRANCISCO S.; CORREA, FERNANDO M. A.; RESSTEL, LEONARDO B. M.. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharmacology Biochemistry and Behavior, v. 99, n. 4, p. 743-748, OCT 2011. (10/17343-0, 07/03685-3)

CAMPOS, ALLINE C.; ORTEGA, ZAIRA; PALAZUELOS, JAVIER; FOGACA, MANOELA V.; AGUIAR, DANIELE C.; DIAZ-ALONSO, JAVIER; ORTEGA-GUTIERREZ, SILVIA; VAZQUEZ-VILLA, HENAR; MOREIRA, FABRICIO A.; GUZMAN, MANUEL; et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 16, n. 6, p. 1407-1419, JUL 2013. (07/03685-3)

SANCHES, S. B.; OSORIO, F. L.; LOUZADA-JUNIOR, P.; MORAES, D.; CRIPPA, J. A. S.; MARTIN-SANTOS, R.. Association between joint hypermobility and anxiety in Brazilian university students: Gender-related differences. JOURNAL OF PSYCHOSOMATIC RESEARCH, v. 77, n. 6, p. 558-561, DEC 2014. (07/03685-3)

SILVA, MICHELLE; AGUIAR, DANIELE C.; DINIZ, CASSIANO R. A.; GUIMARAES, FRANCISCO SILVEIRA; JOCA, SAMIA R. L.. Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions. Cellular and Molecular Neurobiology, v. 32, n. 3, p. 443-453, APR 2012. (07/03685-3)

ISSY, ANA CAROLINA; PEDRAZZI, JOAO FRANCISCO C.; VAN OOSTEN, ANNA BEATRIZ SAITO; CHECHETO, THIAGO; SILVA, RAFAELA R.; NOEL, FRANCOIS; DEL-BEL, ELAINE. Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia. NEUROTOXICITY RESEARCH, SEP 2020. (07/03685-3)

SANCHES, S. B.; OLIVEIRA, G. M.; OSORIO, F. L.; CRIPPA, J. A. S.; MARTIN-SANTOS, R.. Hypermobility and joint hypermobility syndrome in Brazilian students and teachers of ballet dance. RHEUMATOLOGY INTERNATIONAL, v. 35, n. 4, p. 741-747, APR 2015. (07/03685-3)

DE BORTOLI, VALQUIRIA CAMIN; DE MELO YAMASHITA, PAULA SHIMENE; ZANGROSSI, HELIO, JR.. 5-HT1A and 5-HT2A receptor control of a panic-like defensive response in the rat dorsomedial hypothalamic nucleus. JOURNAL OF PSYCHOPHARMACOLOGY, v. 27, n. 12, p. 8-pg., 2013-12-01. (07/03685-3, 08/03123-8)

DE BORTOLI, VALQUIRIA CAMIN; DE MELO YAMASHITA, PAULA SHIMENE; ZANGROSSI, JR., HELIO. 5-HT1A and 5-HT2A receptor control of a panic-like defensive response in the rat dorsomedial hypothalamic nucleus. JOURNAL OF PSYCHOPHARMACOLOGY, v. 27, n. 12, SI, p. 1116-1123, DEC 2013. (08/03123-8, 07/03685-3)

DE REZENDE, MARCOS GONCALVES; GARCIA-LEAL, CYBELE; GRAEFF, FREDERICO GUILHERME; DEL-BEN, CRISTINA MARTA. The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin. JOURNAL OF PSYCHOPHARMACOLOGY, v. 27, n. 12, SI, p. 1124-1133, DEC 2013. (07/03685-3)

MONTEZUMA, KARINA; BIOJONE, CAROLINE; LISBOA, SABRINA F.; CUNHA, FERNANDO Q.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.. Inhibition of iNOS induces antidepressant-like effects in mice: Pharmacological and genetic evidence. Neuropharmacology, v. 62, n. 1, SI, p. 485-491, JAN 2012. (07/03685-3)

ANTONIO WALDO ZUARDI; JOSÉ ALEXANDRE DE SOUZA CRIPPA; JAIME EDUARDO CECÍLIO HALLAK; RICARDO GORAYEB. Human experimental anxiety: actual public speaking induces more intense physiological responses than simulated public speaking. Revista Brasileira de Psiquiatria, v. 35, n. 3, p. 248-253, 2013-09-00. (07/03685-3)

LISBOA, SABRINA F.; REIS, DANIEL G.; DA SILVA, ANDREIA LOPES; CORREA, FERNANDO M. A.; GUIMARAES, FRANCISCO S.; RESSTEL, LEONARDO B. M.. Cannabinoid CB1 receptors in the medial prefrontal cortex modulate the expression of contextual fear conditioning. INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, v. 13, n. 9, p. 1163-1173, OCT 2010. (07/03685-3)

SHUHAMA, ROSANA; RONDINONI, CARLO; DE ARAUJO, DRAULIO BARROS; CAETANO, GUSTAVO DE FREITAS; DOS SANTOS, ANTONIO CARLOS; GRAEFF, FREDERICO GUILHERME; DEL-BEN, CRISTINA MARTA. Behavioral and neuroimaging responses induced by mental imagery of threatening scenarios. Behavioural Brain Research, v. 313, p. 358-369, OCT 15 2016. (07/03685-3)

GAZARINI, L.; STERN, C. A. J.; BERTOGLIO, L. J.. PROTEIN SYNTHESIS IN DORSAL HIPPOCAMPUS SUPPORTS THE DRUG TOLERANCE INDUCED BY PRIOR ELEVATED PLUS-MAZE EXPERIENCE. Neuroscience, v. 179, p. 179-187, APR 14 2011. (07/03685-3)

GOMES, FELIPE V.; ALVES, FERNANDO H. F.; GUIMARAES, FRANCISCO S.; CORREA, FERNANDO M. A.; RESSTEL, LEONARDO B. M.; CRESTANI, CARLOS C.. Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT1A receptor. European Neuropsychopharmacology, v. 23, n. 9, p. 1096-1104, SEP 2013. (11/07332-3, 07/03685-3, 10/16192-8)

HALLAK, JAIME E. C.; MAIA-DE-OLIVEIRA, JOAO PAULO; ABRAO, JOAO; EVORA, PAULO R.; ZUARDI, ANTONIO W.; CRIPPA, JOSE A. S.; BELMONTE-DE-ABREU, PAULO; BAKER, GLEN B.; DURSUN, SERDAR M.. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside A Randomized, Double-blind, Placebo-Controlled Trial. JAMA PSYCHIATRY, v. 70, n. 7, p. 668-676, JUL 2013. (07/03685-3)

STERN, CRISTINA A. J.; GAZARINI, LUCAS; TAKAHASHI, REINALDO N.; GUIMARAES, FRANCISCO S.; BERTOGLIO, LEANDRO J.. On Disruption of Fear Memory by Reconsolidation Blockade: Evidence from Cannabidiol Treatment. NEUROPSYCHOPHARMACOLOGY, v. 37, n. 9, p. 2132-2142, AUG 2012. (07/03685-3)

PEREIRA, VITOR S.; CASAROTTO, PLINIO C.; HIROAKI-SATO, VINICIUS A.; SARTIM, ARIANDRA G.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.. Antidepressant- and anticompulsive-like effects of purinergic receptor blockade: Involvement of nitric oxide. European Neuropsychopharmacology, v. 23, n. 12, p. 1769-1778, DEC 2013. (07/03685-3, 11/17281-7)

LISBOA, S. F.; GUIMARAES, F. S.. Differential role of CB1 and TRPV1 receptors on anandamide modulation of defensive responses induced by nitric oxide in the dorsolateral periaqueductal gray. Neuropharmacology, v. 62, n. 8, p. 2455-2462, JUN 2012. (07/03685-3)

SALES, AMANDA J.; BIOJONE, CAROLINE; TERCETI, MATEUS S.; GUIMARAES, FRANCISCO S.; GOMES, MARCUS V. M.; JOCA, SAMIA R. L.. Antidepressant-like effect induced by systemic and intra-hippocampal administration of DNA methylation inhibitors. British Journal of Pharmacology, v. 164, n. 6, p. 1711-1721, NOV 2011. (07/03685-3)

GOMES, FELIPE V.; RESSTEL, LEONARDO B. M.; GUIMARAES, FRANCISCO S.. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology, v. 213, n. 2-3, p. 465-473, FEB 2011. (07/03685-3)

DE REZENDE, MARCOS GONCALVES; GARCIA-LEAL, CYBELE; GRAEFF, FREDERICO GUILHERME; DEL-BEN, CRISTINA MARTA. The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin. JOURNAL OF PSYCHOPHARMACOLOGY, v. 27, n. 12, p. 10-pg., 2013-12-01. (07/03685-3)

GOMES, FELIPE V.; REIS, DANIEL G.; ALVES, FERNANDO H. F.; CORREA, FERNANDO M. A.; GUIMARAES, FRANCISCO S.; RESSTEL, LEONARDO B. M.. Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. JOURNAL OF PSYCHOPHARMACOLOGY, v. 26, n. 1, p. 10-pg., 2012-01-01. (07/03685-3, 09/03187-9)

MONTEZUMA, KARINA; BIOJONE, CAROLINE; LISBOA, SABRINA F.; CUNHA, FERNANDO Q.; GUIMARAES, FRANCISCO S.; JOCA, SAMIA R. L.. Inhibition of iNOS induces antidepressant-like effects in mice: Pharmacological and genetic evidence. Neuropharmacology, v. 62, n. 1, p. 7-pg., 2012-01-01. (07/03685-3, 09/18372-6)