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  2. Alessandro Guidotti

Alessandro Guidotti MD

Alessandro Guidotti
Designation
  • Scientific Director, Psychiatric Institute
  • Distinguished Professor
Contact Information
  • aguidott@uic.edu
  • (312) 355-5534
  • Neuropsychiatric Institute (NPI)
    912 S. Wood St.
    Department of Psychiatry (MC 913)
    Chicago IL 60612

Alessandro Guidotti is the Scientific Director of the Psychiatric Institute, and Professor of Psychiatry and Biochemistry at the Department of Psychiatry, University of Illinois at Chicago. Prof. Guidotti’s outstanding research record ranges from the report that benzodiazepines, allosterically acting at specific GABAa receptor sites, enhance GABA’s gating of Cl channels dating back to the 1970′s up to his recent pioneer studies on the role of reelin in human cortex and on demethylation of promoters expressed in GABAergic neurons as a potential mechanism of antipsychotic action.

Born August 15, 1936, Florence, Italy. Naturalized U.S. citizen, 1978. M.D., University of Florence, Italy, 1961. Visiting Scientist, Department of Pharmacology, Oxford University, United Kingdom, 1966. Professor of Pharmacology, Department of Pharmacology, University of Florence, Italy, 1968-70. Visiting Associate, Laboratory of Preclinical Pharmacology, NIMH, St Elizabeths Hospital, Washington, DC, 1970-72. Acting Chief, 1973-75, and Chief, 1975-85. Section on Neuroendocrinology, Laboratory of Preclinical Pharmacology, NIMH, St Elizabeths Hospital, Washington DC. Deputy Director, FIDIA-Georgetown Institute for the Neurosciences, Georgetown University, Washington DC, 1985-94. Director, Neuroscience Training Program, Georgetown University, 1992-94. Acting Director, Center for Neuropharmacology, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, 1994-96. Professor, Environmental Medicine, NYU Medical Center, 1995-96. Professor of Psychiatry and Biochemistry, UIC, Department of Psychiatry, Chicago IL, 1996—; Scientific Director, Psychiatric Institute, Department of Psychiatry, UIC, Chicago IL, 2003--; Commissioned Lieutenant, Italian Medical Corp, 1961-62. Fellowship, National Italian Research Council, 1964-65. Privat Docent in Pharmacology, Italian Ministry of Education, 1968. Visiting Scientist, NIMH, 1970-72. Member of the American Society for Pharmacology and Experimental Therapy, 1973. Society for Neuroscience, 1973. International Society for Psychoneuroendocrinology, 1974. International Society of Neurochemistry, 1980. American College of Neuropsychopharmacology, 1989. Collegium Internationale Neuro-Psychopharmacologicum, 1989. American Society of Neurochemistry, 1993, Distinguished Professors, University of Illinois at Chicago, 2011.

  • Research Contributions

    In the 1970s, Guidotti demonstrated that the trans-synaptic induction of tyrosine-hydroxylase depends on the nuclear translocation of protein-kinaseA catalytic subunits and the phosphorylation of specific nuclear proteins (1).

    Together with Costa (1975), he reported that benzodiazepines, allosterically acting at specific GABAA receptor sites, enhance GABA’s gating of Cl- channels (3,4). Pursuing this research trend, he discovered imidazenil, an imidazo-benzodiazepine acting as a selective positive allosteric modulator at GABAA receptors. Unlike other benzodiazepines, imidazenil is devoid of tolerance or dependence liabilities and may become the drug of choice to treat psychoses associated with GABAergic dysfunction (4-6). He also discovered (1990s) that SSRIs preferentially facilitate GABA's action at GABAA receptors by increasing brain neurosteroid content with potency greater than 5HT-reuptake inhibition (7).

    Guidotti and his co-investigators (1998-2000) pioneered studies on the role of reelin in human cortex. Reelin is synthesized and secreted from GABAergic neurons into the extracellular matrix. He demonstrated that reelin acting at integrin receptors facilitates the translation of mRNAs located in dendrites of cortical pyramidal neurons (8). In cortical GABAergic neurons of schizophrenia patients, reelin and GAD67 expressions are downregulated (8), very likely by epigenetic promoter hypermethylation (9-12) related to high-order chromatin remodeling dysfunctions. Guidotti and collaborators recently discovered that valproate, an effective coadjuvant in psychosis treatment, inhibits brain chromatin histone deacetylases and promotes histone tail acetylation thereby downregulating methylation of promoters expressed by cortical GABAergic neurons (11). He proposes that demethylation of promoters expressed in GABAergic neurons could be a mechanism operative in the antipsychotic action of valproate (11,12).


  • ORIGINAL PUBLICATIONS IN PEER-REVIEWED JOURNALS

    1973 Guidotti A, Costa E. Involvement of adenosine 3',5' monophosphate in the activation of tyrosine hydroxylase elicited by drugs. Science 179: 902 904.

    1976 Gale K, Guidotti A. GABA mediated control of rat neostriatal tyrosine hydroxylase revealed by the use of intranigral muscimol. Nature 263: 691 693.

    1977 Biggio G, Brodie BB, Costa E, Guidotti A. Mechanisms by which diazepam, muscimol and other drugs change the content of cGMP in cerebellar cortex. Proc Natl Acad Sci USA 74: 3592 3596.

    1979 Costa E, Guidotti A. Molecular mechanisms in the receptor action of benzodiazepines. In Okun GR, Cho AK (eds) Ann Rev Pharmacol Toxicol 19: 531 545.

    1985 Alho H, Costa E, Ferrero P, Fujimoto M, Cosenza-Murphy D, Guidotti A. Diazepam binding inhibitor: a neuropeptide located in selected neuronal populations of rat brain. Science 229: 179-182.

    1989 Sprengel R, Werner P, Seeburg PH, Mukhin AG, Santi MR, Grayson DR, Guidotti A, Krueger KE. Molecular cloning and expression of cDNA encoding a peripheral-type benzodiazepine receptor. J Biol Chem 264: 20415 20421.

    1998 Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A. Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 95: 3239-3244.

    2000 Guidotti A, Auta J, Davis JM, Dwivedi Y, DiGiorgi VD, Impagnatiello F, Pandey GN, Pesold C, Sharma R, Uzunov DP, Costa E. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. A postmortem brain study. Arch Gen Psych 57: 1061-1069.

    2005 Veldic M, Guidotti A, Maloku E, Davis JM, Costa E. In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc Natl Acad Sci USA 102 2152-2157.

    2007 Ruzicka W, Zhubi A, Veldic M, Grayson DR, Costa E, Guidotti A. (2007) Selective epigenetic alteration of layer I GABAergic neurons isolated from prefrontal cortex of schizophrenia patients using laser-assisted microdissection. Mol Psychiatry 12:385-397.

    2009 Guidotti A, Dong E, Kundakovic M, Satta R, Grayson DR, Costa E. Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling. Trend Pharmacol 30:55-60

    2011 Guidotti A, Auta J, Chen Y, Davis JM, Dong E, Gavin DP, Grayson DR, Matrisciano F, Pinna G, Satta R, Sharma RP, Tremolizzo L, Tueting P. Epigenetic GABAergic targets in schizophrenia and bipolar disorder. Neuropharmacology 60:7-8):1007-1016.

Title Description Investigator(s) Category Status
Better DNA Methyltransferase (DNMT) Inhibitors Correct the Behavioral and Molecular Endophentoypes of an Animal Model of Psychosis Progress in developing new, more effective, and less toxic drugs to treat the complex symptomatology of schizophrenia and bipolar disorder has been hampered by the lack of objective diagnostic tools to assess prodromes, progression severity, and therapeutic responses to drugs. Laboratory of Molecular Neuroscience On-going
Chronic Alcohol Exposure Differentially Alters the Levels of S-Adenosyl Methionine (SAM) and S-Adenosyl Homocysteine in the Rat Brain Chronic alcohol exposure leads to behavioral changes, as well as, decreased expression of genes associated with synaptic plasticity. In this project, we treat rats chronically with alcohol and also subject a group of these to alcohol withdrawal. Psychiatric Institute On-going
DNA Methylation in the Etiopathogenesis of Schizophrenia (SZ) DNA methylation is an important epigenetic mark that plays a prominent role in regulating gene expression during development of the brain. For the last twenty years, we have been investigating the role of DNA methylation in regulating candidate genes that are down-regulated in SZ. Laboratory of Molecular Neuroscience On-going
DNA-mthylation/demethylation networks in brain of alcoholic subjects The objectives of this research project are to investigate the expression and promoter binding of components of the DNA-methylation and DNA-demethylation networks in cortico-limbic structures [prefrontal cortex (PFC), hippocampus, and amygdala] of post-mortem brains of alcoholics (compared with age/sex matched control subjects). Alcohol Research Center On-going
Epigenetic mechanisms Operative in Psychotic Disorders As part of our ongoing studies on the etiopathogenesis of schizophrenia and psychosis-related disorders, we have developed an animal model that mimics some of the behavioral and molecular endophenotypes associated with these disorders. Psychiatric Institute On-going
One Carbon Metabolism and DNA Methylation Enrichment in Subjects with Alcohol Use Disorders DNA methylation is an important epigenetic mark that plays a prominent role in regulating gene expression in mature adult brain. Recent studies in the cerebellum and frontal cortex of Alcohol Use Disorder subjects have shown altered epigenetic regulation of selected genes unique to each brain region. Psychiatric Institute On-going