Participation of glutamate and nitric oxide on the pathophysiology of neuropsychiatry disorders

• Grant number: 02/13197-2
• Support Opportunities: Research Projects - Thematic Grants
• Duration: August 01, 2003 - November 30, 2007
• 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 ; Frederico Guilherme Graeff ; Hélio Zangrossi Júnior
• Associated grant(s): 05/55396-0 - Inhibition of neuronal nitric oxide synthase in the hippocampus induces antidepressant-like effects., AR.EXT
• Associated scholarship(s): 05/02054-4 - Participation of glutamate and nitric oxide on the pathophysiology of neuropsychiatry disorders, BP.TT

Abstract

Glutamate is well recognized as the main excitatory neurotransmitter in the mammalian central nervous system. Its receptors are classified into ionotropic and metabotropic. Whereas 8 subtypes of the former have already bee recognized, ionotropic glutamate receptors are usually divided into NMDA, AMP A and Kainic subtypes. Glutamate activation of NMDA receptors leads to calcium influx, activation of nitric oxide synthase (NOS) and formation of nitric oxide (NO). In the last decade our group has proposed the participation of glutamate/NO mediated neurotransmission in several neuropsychiatry disorders and brain functions. The main objective of the present project is to continue the investigation of a possible glutamate/NO role on anxiety, affective, motor and psychotic disorders. We also want to test new possible therapeutic approaches to these disorders based on pharmacological interventions on glutamate/NO mediated neurotransmission.Six main groups of projects are proposed. The first four groups are related to pre-clinical studies on animal models (e.g. elevated plus maze, learned helplessness, predator exposure, electrical and/or chemical stimulation of aversive areas, pre-pulse inhibition, catalepsy, motor lesions) and/or Studies of the molecular changes induced by such models or by glutamate/NO related drugs. The last two groups of studies involve clinical research on volunteers and/or patients exposed to models of anxiety (public speaking) or psychosis (ketamine administration) and non-invasive evaluation methods (magnetic resonance imaging, spectroscopy and salivary cortisol evaluation). Considering our previous studies and results from the literature suggesting an interaction between glutamatergic and endocannabinoid systems on psychosis, we will also evaluate a possible antipsychotic effect of cannabidiol, a component of Cannabis sativa. (AU)

Scientific publications

(35)

(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)

RICARDO R. UCHIDA; CRISTINA M. DEL-BEN; DAVID ARAÚJO; GERALDO BUSATTO-FILHO; FÁBIO L.S. DURAN; JOSÉ A.S. CRIPPA; FREDERICO G. GRAEFF. Correlation between voxel based morphometry and manual volumetry in magnetic resonance images of the human brain. Anais da Academia Brasileira de Ciências, v. 80, n. 1, p. 149-156, 2008-03-00. (02/13197-2)

SIMONE H. PINHEIRO; HÉLIO ZANGROSSI-JR.; CRISTINA M. DEL-BEN; FREDERICO G. GRAEFF. Elevated mazes as animal models of anxiety: effects of serotonergic agents. Anais da Academia Brasileira de Ciências, v. 79, n. 1, p. 71-85, 2007-03-00. (02/13197-2)

ZUARDI, A. W.; CRIPPA, J. A. S.; HALLAK, J. E. C.; PINTO, J. P.; CHAGAS, M. H. N.; RODRIGUES, G. G. R.; DURSUN, S. M.; TUMAS, V.. Cannabidiol for the treatment of psychosis in Parkinson's disease. JOURNAL OF PSYCHOPHARMACOLOGY, v. 23, n. 8, p. 979-983, NOV 2009. (02/13197-2)

CRIPPA, JOSE ALEXANDRE; ZUARDI, ANTONIO WALDO; MARTIN-SANTOS, ROCIO; BHATTACHARYYA, SAGNIK; ATAKAN, ZERRIN; MCGUIRE, PHILIP; FUSAR-POLI, PAOLO. Cannabis and anxiety: a critical review of the evidence. HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL, v. 24, n. 7, p. 515-523, OCT 2009. (02/13197-2)

SERGIO ISHARA; MARINA BANDEIRA; ANTONIO WALDO ZUARDI. Equipes de serviços psiquiátricos públicos: avaliação da satisfação. Revista Brasileira de Psiquiatria, v. 30, n. 1, p. 38-41, 2007-12-20. (02/13197-2)

R.F. SANCHES; J.A.S. CRIPPA; J.E.C. HALLAK; J.P.M. DE SOUSA; D. ARAÚJO; A.C. SANTOS; A.W. ZUARDI. Proton magnetic resonance spectroscopy of the frontal, cingulate and perirolandic cortices and its relationship to skin conductance in patients with schizophrenia. Brazilian Journal of Medical and Biological Research, v. 41, n. 12, p. 1132-1141, 2008-12-00. (02/13197-2)

MOREIRA, FABRICIO DE ARAÚJO; MOLCHANOV, MORIANA LUDMILLA; GUIMARÃES, FRANCISCO SILVEIRA. Ionotropic glutamate-receptor antagonists inhibit the aversive effects of nitric oxide donor injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology, v. 171, n. 2, p. 199-203, Jan. 2004. (02/13197-2)

CRIPPA, JOSE ALEXANDRE S.; DERENUSSON, GUILHERME NOGUEIRA; FERRARI, THIAGO BORDUQUI; WICHERT-ANA, LAURO; DURAN, FABIO L. S.; MARTIN-SANTOS, ROCIO; SIMOES, MARCUS VINICIUS; BHATTACHARYYA, SAGNIK; FUSAR-POLI, PAOLO; ATAKAN, ZERRIN; et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. JOURNAL OF PSYCHOPHARMACOLOGY, v. 25, n. 1, p. 121-130, JAN 2011. (02/13197-2)

MOREIRA‚ F. A.; GUIMARÃES‚ F. S.. Benzodiazepine receptor and serotonin 2A receptor modulate the aversive-like effects of nitric oxide in the dorsolateral periaqueductal gray of rats. Psychopharmacology, v. 176, n. 3/4, p. 362-368, Nov. 2004. (02/13197-2)

BERTOGLIO‚ L.J.; JOCA‚ S.R.L.; GUIMARÃES‚ F.S.. Further evidence that anxiety and memory are regionally dissociated within the hippocampus. Behavioural Brain Research, v. 175, n. 1, p. 183-188, 2006. (02/13197-2)

BERTOGLIO‚ L.J.; ZANGROSSI‚ H.; OTHERS. Involvement of dorsolateral periaqueductal gray cholecystokinin-2 receptors in the regulation of a panic-related behavior in rats. Brain Research, v. 1059, n. 1, p. 46-51, 2005. (02/13197-2)

BERTOGLIO‚ L.J.; CAROBREZ‚ A.P.. Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats. Psychopharmacology, v. 170, n. 4, p. 335-342, 2003. (02/13197-2)

BERTOGLIO‚ L.J.; DE BORTOLI‚ V.C.; ZANGROSSI JR‚ H.. Cholecystokinin-2 receptors modulate freezing and escape behaviors evoked by the electrical stimulation of the rat dorsolateral periaqueductal gray. Brain Research, v. 1156, p. 133-138, 2007. (02/13197-2)

BERTOGLIO‚ LJ; GUIMARAES‚ FS; ZANGROSSI‚ H.. Lack of interaction between NMDA and cholecystokinin-2 receptor-mediated neurotransmission in the dorsolateral periaqueductal gray in the regulation of rat defensive behaviors. Life Sciences, v. 79, n. 23, p. 2238-2244, 2006. (02/13197-2)

JOCA‚ S.R.L.; ZANELATI‚ T.; GUIMARÃES‚ F.S.. Post-stress facilitation of serotonergic‚ but not noradrenergic‚ neurotransmission in the dorsal hippocampus prevents learned helplessness development in rats. Brain Research, v. 1087, n. 1, p. 67-74, 2006. (02/13197-2)

BEIJAMINI‚ V.; GUIMARÃES‚ F.S.. Activation of neurons containing the enzyme nitric oxide synthase following exposure to an elevated plus maze. Brain Research Bulletin, v. 69, n. 4, p. 347-355, 2006. (02/13197-2)

BEIJAMINI‚ V.; GUIMARÃES‚ F.S.. c-Fos expression increase in NADPH-diaphorase positive neurons after exposure to a live cat. Behavioural Brain Research, v. 170, n. 1, p. 52-61, 2006. (02/13197-2)

PARENTE‚ A.C.B.V.; GARCIA-LEAL‚ C.; DEL-BEN‚ C.M.; GUIMARÃES‚ F.S.; GRAEFF‚ F.G.. Subjective and neurovegetative changes in healthy volunteers and panic patients performing simulated public speaking. European Neuropsychopharmacology, v. 15, n. 6, p. 663-671, 2005. (02/13197-2)

JOSÉ ALEXANDRE CRIPPA; ACIOLY L T LACERDA; EDSON AMARO; GERALDO BUSATTO FILHO; ANTONIO WALDO ZUARDI; RODRIGO A BRESSAN. Efeitos cerebrais da maconha: resultados dos estudos de neuroimagem. Revista Brasileira de Psiquiatria, v. 27, n. 1, p. 70-78, 2005-03-00. (02/13197-2)

ROSANA SHUHAMA; CRISTINA M. DEL-BEN; SÔNIA R. LOUREIRO; FREDERICO G. GRAEFF. Animal defense strategies and anxiety disorders. Anais da Academia Brasileira de Ciências, v. 79, n. 1, p. 97-109, 2007-03-00. (02/13197-2)

J.A.S. CRIPPA; R. UCHIDA; G.F. BUSATTO; F.S. GUIMARÃES; C.M. DEL-BEN; A.W. ZUARDI; A.C. SANTOS; D. ARAÚJO; P.K. MCGUIRE; F.G. GRAEFF. The size and prevalence of the cavum septum pellucidum are normal in subjects with panic disorder. Brazilian Journal of Medical and Biological Research, v. 37, n. 3, p. 371-374, 2004-03-00. (98/10639-7, 99/12205-7, 02/13197-2)

DE OLIVEIRA, DANIELLE C. G.; ZUARDI, ANTONIO W.; GRAEFF, FREDERICO G.; QUEIROZ, REGINA H. C.; CRIPPA, JOSE A. S.. Anxiolytic-like effect of oxytocin in the simulated public speaking test. JOURNAL OF PSYCHOPHARMACOLOGY, v. 26, n. 4, p. 497-504, APR 2012. (02/13197-2)

ZUARDI, A. W.; CRIPPA, J. A. S.; DURSUN, S. M.; MORAIS, S. L.; VILELA, J. A. A.; SANCHES, R. F.; HALLAK, J. E. C.. Cannabidiol was ineffective for manic episode of bipolar affective disorder. JOURNAL OF PSYCHOPHARMACOLOGY, v. 24, n. 1, p. 135-137, JAN 2010. (02/13197-2)

VALVASSORI, SAMIRA S.; ELIAS, GUILHERME; DE SOUZA, BRUNA; PETRONILHO, FABRICIA; DAL-PIZZOL, FELIPE; KAPCZINSKI, FLAVIO; TRZESNIAK, CLARISSA; TUMAS, VITOR; DURSUN, SERDAR; NISIHARA CHAGAS, MARCOS HORTES; et al. Effects of cannabidiol on amphetamine-induced oxidative stress generation in an animal model of mania. JOURNAL OF PSYCHOPHARMACOLOGY, v. 25, n. 2, p. 274-279, FEB 2011. (02/13197-2)

CRIPPA‚ J.A.S.; ZUARDI‚ A.W.; BUSATTO‚ G.F.; SANCHES‚ R.F.; SANTOS‚ A.C.; ARAÚJO‚ D.; AMARO‚ E.; HALLAK‚ J.E.C.; NG‚ V.; MCGUIRE‚ P.K.. Cavum septum pellucidum and adhesio interthalamica in schizophrenia: an MRI study. EUROPEAN PSYCHIATRY, v. 21, n. 5, p. 291-299, 2006. (98/10639-7, 99/12205-7, 02/13197-2)

BERTOGLIO‚ L.J.; ANZINI‚ C.; LINO-DE-OLIVEIRA‚ C.; CAROBREZ‚ A.P.. Enhanced dorsolateral periaqueductal gray activity counteracts the anxiolytic response to midazolam on the elevated plus-maze Trial 2 in rats. Behavioural Brain Research, v. 162, n. 1, p. 99-107, 2005. (02/13197-2)

DE LIMA OSÓRIO‚ F.; CRIPPA‚ J.A.; LOUREIRO‚ S.R.. A study of the discriminative validity of a screening tool (MINI-SPIN) for social anxiety disorder applied to Brazilian university students. EUROPEAN PSYCHIATRY, v. 22, n. 4, p. 239-243, 2007. (02/13197-2)

BERTOGLIO‚ L.J.; ZANGROSSI JR‚ H.. Involvement of dorsolateral periaqueductal gray N-methyl-D-aspartic acid glutamate receptors in the regulation of risk assessment and inhibitory avoidance behaviors in the rat elevated T-maze. Behavioural Pharmacology, v. 17, n. 7, p. 589, 2006. (02/13197-2)

GOMES‚ M.Z.; RAISMAN-VOZARI‚ R.; DEL BEL‚ E.A.. A nitric oxide synthase inhibitor decreases 6-hydroxydopamine effects on tyrosine hydroxylase and neuronal nitric oxide synthase in the rat nigrostriatal pathway. Brain Research, v. 1203, p. 160-169, 2008. (02/13197-2)

GARCIA-LEAL‚ C.; PARENTE‚ A.C.B.V.; DEL-BEN‚ C.M.; GUIMARÃES‚ F.S.; MOREIRA‚ A.C.; ELIAS‚ L.L.K.; GRAEFF‚ F.G.. Anxiety and salivary cortisol in symptomatic and nonsymptomatic panic patients and healthy volunteers performing simulated public speaking. PSYCHIATRY RESEARCH, v. 133, n. 2-3, p. 239-252, 2005. (02/13197-2)

DOS SANTOS‚ L.; DE ANDRADE‚ T.G.C.S.; ZANGROSSI JUNIOR‚ H.. 5-HT1A receptors in the dorsal hippocampus mediate the anxiogenic effect induced by the stimulation of 5-HT neurons in the median raphe nucleus. European Neuropsychopharmacology, v. 18, n. 4, p. 286-294, 2008. (02/13197-2)

CRIPPA, JOSE ALEXANDRE S.; OSORIO, FLAVIA DE LIMA; DEL-BEN, CRISTINA MARTA; SANTOS FILHO, ALAOR; DA SILVA FREITAS, MARIA CECILIA; LOUREIRO, SONIA REGINA. Comparability between telephone and face-to-face Structured Clinical Interview for DSM-IV in assessing social anxiety disorder. PERSPECTIVES IN PSYCHIATRIC CARE, v. 44, n. 4, p. 241-247, OCT 2008. (02/13197-2)

GUIMARÃES, F. S.; MOREIRA, F. A.; AGUIAR, D. C.; DE LUCCA, A. C. B.; BEIJAMINI, V.. Role of nitric oxide in brain regions related to defensive reactions. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 29, n. 8, p. 1313-1322, 2005. (02/13197-2)

CAROBREZ, A. P.; BERTOGLIO, L. J.. Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 29, n. 8, p. 1193-1205, 2005. (02/13197-2)

MOREIRA, FABRÍCIO DE ARAÚJO; GUIMARÃES, FRANCISCO SILVEIRA. Role of serotonin receptors in panic-like behavior induced by nitric oxide in the rat dorsolateral periaqueductal gray: effects of chronic clomipramine treatment. Life Sciences, v. 77, n. 16, p. 1972-1982, 2005. (02/13197-2)