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Xavier Guitart-Navarro, Ph.D.

Xavier Guitart, Ph.D.

Position

Former Staff Scientist, Integrative Neurobiology Section

Contact

Triad Technology Center
333 Cassell Drive
Room 4500
Baltimore, MD 21224

Education

Ph.D. – Cell Biology Department, University of Barcelona (Catalonia)

B.Sc.- Biology, University of Barcelona

Research Interests

Xavier Guitart received his B.Sc. from the University of Barcelona in Catalonia in 1977. As a Ph.D. student, he investigated the role of protein phosphorylation in neurotransmitter release.  In 1983 he worked at the Institute of Psychiatry in London under the supervision of Professor Richard Rodnight.  He received his Ph.D. in Neurosciences in 1987. He accepted a Post-doctoral fellow – Associate Researcher position in the laboratory of Eric J. Nestler at Yale University where he studied protein phosphorylation linked to drug addiction. In 1993 he worked in the private sector as the director of biological discovery at Esteve Inc. In 2008, he worked at the National Institute of Mental Health in Bethesda (MD), and in 2011 accepted his current position as a Staff Scientist at the NIDA/IRP.

I am interested in understanding the brain circuits involved in substance use disorders (SUD). My research consists of studying GPCR heteromers as targets for the development of new molecules that can be used to treat psychiatric disorders. Specifically, I am focused on studying the dopamine-1(D1) and dopamine-3 (D3) receptors.  It is well documented that these receptors form heteromers, and that the density of D3 receptors is altered after chronic psychostimulants administration, specifically cocaine.  The study of this heteremer is important not only for the understanding of addiction, but  for understanding other psychiatric disorders that share similar brain circuits, and that also show substantial changes in the density of D1 and D3 dopamine receptors over time.

Selected Publications

2016

Guitart, Xavier; Bonaventura, Jordi; Rea, William; Orru, Marco; Cellai, Lucrezia; Dettori, Ilaria; Pedata, Felicita; Brugarolas, Marc; Cortes, Antonio; Casado, Vicent; Chang, Ching-Pang; Narayanan, Manikandan; Chern, Yijuang; Ferre, Sergi

Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease. Journal Article

In: Neurobiol Dis, vol. 96, pp. 47–53, 2016, ISSN: 1095-953X (Electronic); 0969-9961 (Linking).

Abstract | Links | BibTeX

@article{Guitart:2016aa,
title = {Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease.},
author = {Xavier Guitart and Jordi Bonaventura and William Rea and Marco Orru and Lucrezia Cellai and Ilaria Dettori and Felicita Pedata and Marc Brugarolas and Antonio Cortes and Vicent Casado and Ching-Pang Chang and Manikandan Narayanan and Yijuang Chern and Sergi Ferre},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27567601},
doi = {10.1016/j.nbd.2016.08.013},
issn = {1095-953X (Electronic); 0969-9961 (Linking)},
year = {2016},
date = {2016-12-01},
journal = {Neurobiol Dis},
volume = {96},
pages = {47--53},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States.},
abstract = {The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [(3)H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse. In view of the crucial role of the equilibrative nucleoside transporter (ENT1) in determining extracellular content of adenosine, the binding properties of the ENT1 inhibitor [(3)H]-S-(4-Nitrobenzyl)-6-thioinosine were evaluated in zQ175 mice and the differential expression and differential coexpression patterns of the ENT1 gene (SLC29A1) were analyzed in a large human cohort of HD disease and controls. Extracellular striatal levels of adenosine were significantly lower in both animal models as compared with control littermates and striatal ENT1 binding sites were significantly upregulated in zQ175 mice. ENT1 transcript was significantly upregulated in HD disease patients at an early neuropathological severity stage, but not those with a higher severity stage, relative to non-demented controls. ENT1 transcript was differentially coexpressed (gained correlations) with several other genes in HD disease subjects compared to the control group. The present study demonstrates that ENT1 and adenosine constitute biomarkers of the initial stages of neurodegeneration in HD disease and also predicts that ENT1 could constitute a new therapeutic target to delay the progression of the disease.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/27567601
  • doi:10.1016/j.nbd.2016.08.013

Close

2014

Ferre, Sergi; Casado, Vicent; Devi, Lakshmi A; Filizola, Marta; Jockers, Ralf; Lohse, Martin J; Milligan, Graeme; Pin, Jean-Philippe; Guitart, Xavier

G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Journal Article

In: Pharmacol Rev, vol. 66, no. 2, pp. 413–434, 2014, ISSN: 1521-0081 (Electronic); 0031-6997 (Linking).

Abstract | Links | BibTeX

@article{Ferre:2014aa,
title = {G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives.},
author = {Sergi Ferre and Vicent Casado and Lakshmi A Devi and Marta Filizola and Ralf Jockers and Martin J Lohse and Graeme Milligan and Jean-Philippe Pin and Xavier Guitart},
url = {https://www.ncbi.nlm.nih.gov/pubmed/24515647},
doi = {10.1124/pr.113.008052},
issn = {1521-0081 (Electronic); 0031-6997 (Linking)},
year = {2014},
date = {2014-02-10},
journal = {Pharmacol Rev},
volume = {66},
number = {2},
pages = {413--434},
address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes on Drug Abuse, Department of Health and Human Services, 333 Cassell Drive, Baltimore, Maryland 21224. sferre@intra.nida.nih.gov.},
abstract = {Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/24515647
  • doi:10.1124/pr.113.008052

Close

2004

Guitart, Xavier; Codony, Xavier; Monroy, Xavier

Sigma receptors: biology and therapeutic potential. Journal Article

In: Psychopharmacology (Berl), vol. 174, no. 3, pp. 301–319, 2004, ISSN: 0033-3158 (Print); 0033-3158 (Linking).

Abstract | Links | BibTeX

@article{Guitart:2004aa,
title = {Sigma receptors: biology and therapeutic potential.},
author = {Xavier Guitart and Xavier Codony and Xavier Monroy},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15197533},
doi = {10.1007/s00213-004-1920-9},
issn = {0033-3158 (Print); 0033-3158 (Linking)},
year = {2004},
date = {2004-07-01},
journal = {Psychopharmacology (Berl)},
volume = {174},
number = {3},
pages = {301--319},
address = {Biological Discovery and CNS Research Department, Research Center, Esteve, S.A., Mare de Deu de Montserrat 221, 08041 Barcelona, Spain. xguitart@esteve.es},
abstract = {More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/15197533
  • doi:10.1007/s00213-004-1920-9

Close

1989

Guitart, X; Nestler, E J

Identification of morphine- and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of rat brain: regulation by acute and chronic morphine. Journal Article

In: J Neurosci, vol. 9, no. 12, pp. 4371–4387, 1989, ISSN: 0270-6474 (Print); 0270-6474 (Linking).

Abstract | Links | BibTeX

@article{Guitart:1989aa,
title = {Identification of morphine- and cyclic AMP-regulated phosphoproteins (MARPPs) in the locus coeruleus and other regions of rat brain: regulation by acute and chronic morphine.},
author = {X Guitart and E J Nestler},
url = {https://www.ncbi.nlm.nih.gov/pubmed/2556507},
issn = {0270-6474 (Print); 0270-6474 (Linking)},
year = {1989},
date = {1989-12-01},
journal = {J Neurosci},
volume = {9},
number = {12},
pages = {4371--4387},
address = {Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.},
abstract = {Regulation of cAMP-dependent protein phosphorylation by acute and chronic morphine was studied in the rat locus coeruleus (LC), a brain region that appears to play an important role in mediating morphine action in animals, including humans. Rats were treated chronically with morphine under conditions known to induce states of tolerance and dependence. Protein phosphorylation was then studied in extracts of LC and other brain regions with back-phosphorylation assays under different conditions and with 1- and 2-dimensional electrophoretic procedures. Evidence was obtained to suggest that chronic morphine increased the phosphorylation state of proteins of 165, 55, and 14-20 kDa and increased the total amount of proteins of 145, 71, 62, 58, and 51 kDa in the LC. Concomitant treatment of rats with naltrexone, an opiate receptor antagonist, blocked the ability of morphine to influence each of these proteins, indicating that morphine regulation of protein phosphorylation occurred through the specific activation of opiate receptors. Regulation of 165, 71, 62, 58, 55, and 51 kDa by chronic morphine was specific to the LC among the brain regions studied, whereas regulation of 145 and 14-20 kDa was also observed in the frontal cortex, neostriatum, and dorsal raphe. Most of the phosphoproteins whose phosphorylation state or total amount was increased by chronic morphine treatment in the LC in vivo were also shown to have their phosphorylation state decreased by acute morphine treatment in isolated LC nuclei ex vivo. In addition, the phosphorylation state of most of these morphine-regulated phosphoproteins was stimulated by forskolin or cAMP analogs in isolated LC and by cAMP in broken cell preparations of this brain region, supporting the view that these proteins are physiological substrates for cAMP-dependent protein kinase in the LC. Phosphoproteins regulated by morphine and cAMP were designated "MARPPs," morphine- and cAMP-regulated phosphoproteins, whereas those regulated by morphine but not by cAMP were designated "MRPPs." Taken together, the results of this study indicate that chronic morphine produces specific alterations in cAMP-dependent protein phosphorylation in the LC and raise the possibility that regulation of these specific phosphoproteins contributes to the development of tolerance and/or dependence in these neurons.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

Close

Regulation of cAMP-dependent protein phosphorylation by acute and chronic morphine was studied in the rat locus coeruleus (LC), a brain region that appears to play an important role in mediating morphine action in animals, including humans. Rats were treated chronically with morphine under conditions known to induce states of tolerance and dependence. Protein phosphorylation was then studied in extracts of LC and other brain regions with back-phosphorylation assays under different conditions and with 1- and 2-dimensional electrophoretic procedures. Evidence was obtained to suggest that chronic morphine increased the phosphorylation state of proteins of 165, 55, and 14-20 kDa and increased the total amount of proteins of 145, 71, 62, 58, and 51 kDa in the LC. Concomitant treatment of rats with naltrexone, an opiate receptor antagonist, blocked the ability of morphine to influence each of these proteins, indicating that morphine regulation of protein phosphorylation occurred through the specific activation of opiate receptors. Regulation of 165, 71, 62, 58, 55, and 51 kDa by chronic morphine was specific to the LC among the brain regions studied, whereas regulation of 145 and 14-20 kDa was also observed in the frontal cortex, neostriatum, and dorsal raphe. Most of the phosphoproteins whose phosphorylation state or total amount was increased by chronic morphine treatment in the LC in vivo were also shown to have their phosphorylation state decreased by acute morphine treatment in isolated LC nuclei ex vivo. In addition, the phosphorylation state of most of these morphine-regulated phosphoproteins was stimulated by forskolin or cAMP analogs in isolated LC and by cAMP in broken cell preparations of this brain region, supporting the view that these proteins are physiological substrates for cAMP-dependent protein kinase in the LC. Phosphoproteins regulated by morphine and cAMP were designated "MARPPs," morphine- and cAMP-regulated phosphoproteins, whereas those regulated by morphine but not by cAMP were designated "MRPPs." Taken together, the results of this study indicate that chronic morphine produces specific alterations in cAMP-dependent protein phosphorylation in the LC and raise the possibility that regulation of these specific phosphoproteins contributes to the development of tolerance and/or dependence in these neurons.

Close

  • https://www.ncbi.nlm.nih.gov/pubmed/2556507

Close

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