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GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA(A)Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampa...

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Autores principales: Marques, Tiago Reis, Ashok, Abhishekh H., Angelescu, Ilinca, Borgan, Faith, Myers, Jim, Lingford-Hughes, Anne, Nutt, David J., Veronese, Mattia, Turkheimer, Federico E., Howes, Oliver D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440185/
https://www.ncbi.nlm.nih.gov/pubmed/32296127
http://dx.doi.org/10.1038/s41380-020-0711-y
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author Marques, Tiago Reis
Ashok, Abhishekh H.
Angelescu, Ilinca
Borgan, Faith
Myers, Jim
Lingford-Hughes, Anne
Nutt, David J.
Veronese, Mattia
Turkheimer, Federico E.
Howes, Oliver D.
author_facet Marques, Tiago Reis
Ashok, Abhishekh H.
Angelescu, Ilinca
Borgan, Faith
Myers, Jim
Lingford-Hughes, Anne
Nutt, David J.
Veronese, Mattia
Turkheimer, Federico E.
Howes, Oliver D.
author_sort Marques, Tiago Reis
collection PubMed
description A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA(A)Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA(A)Rs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA(A)Rs are altered in vivo or related to symptoms. We investigated α5-GABA(A)Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [(11)C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [(11)C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [(11)C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (V(T)) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 V(T) in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [(11)C]Ro15-4513 V(T) and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.
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spelling pubmed-84401852021-09-17 GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513 Marques, Tiago Reis Ashok, Abhishekh H. Angelescu, Ilinca Borgan, Faith Myers, Jim Lingford-Hughes, Anne Nutt, David J. Veronese, Mattia Turkheimer, Federico E. Howes, Oliver D. Mol Psychiatry Article A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABA(A)Rs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABA(A)Rs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABA(A)Rs are altered in vivo or related to symptoms. We investigated α5-GABA(A)Rs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [(11)C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [(11)C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [(11)C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (V(T)) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 V(T) in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [(11)C]Ro15-4513 V(T) and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder. Nature Publishing Group UK 2020-04-15 2021 /pmc/articles/PMC8440185/ /pubmed/32296127 http://dx.doi.org/10.1038/s41380-020-0711-y Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Marques, Tiago Reis
Ashok, Abhishekh H.
Angelescu, Ilinca
Borgan, Faith
Myers, Jim
Lingford-Hughes, Anne
Nutt, David J.
Veronese, Mattia
Turkheimer, Federico E.
Howes, Oliver D.
GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title_full GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title_fullStr GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title_full_unstemmed GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title_short GABA-A receptor differences in schizophrenia: a positron emission tomography study using [(11)C]Ro154513
title_sort gaba-a receptor differences in schizophrenia: a positron emission tomography study using [(11)c]ro154513
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440185/
https://www.ncbi.nlm.nih.gov/pubmed/32296127
http://dx.doi.org/10.1038/s41380-020-0711-y
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