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Andersson P, Li X, Persson J. Hippocampal and prefrontal GABA and glutamate concentration contribute to component processes of working memory in aging. Cereb Cortex 2025; 35:bhaf105. [PMID: 40350714 PMCID: PMC12066406 DOI: 10.1093/cercor/bhaf105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/18/2025] [Accepted: 04/04/2025] [Indexed: 05/14/2025] Open
Abstract
Both animal and human studies indicate that individual variation in the neurometabolites gamma-aminobutyric acid and glutamate is linked to cognitive function. Age-related differences in these neurometabolites could potentially explain lower cognitive ability in older age. Working memory-the capacity to hold a limited amount of information online for a short period-has a central role in cognition, and this ability is also impaired in older individuals. Here, we investigated the relationship between gamma-aminobutyric acid (GABA+) levels and a composite measure of glutamate/glutamine (Glx) in the hippocampus and inferior frontal gyrus (IFG) and how these neurochemical markers relate to working memory in younger and older adults. Across age groups, we found a significant positive association between working memory accuracy and Glx in the IFG, as well as a significant negative association between GABA+ in this region and proactive interference. Age-stratified analyses demonstrated significant positive associations between components of working memory and hippocampal/IFG Glx, as well as a significant negative association between IFG GABA+ and proactive interference in older adults only. These results provide novel evidence for a specific involvement of excitatory Glx and working memory accuracy as well as inhibitory GABA+ for control of proactive interference in working memory, and how these effects are differentially affected by age.
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Affiliation(s)
- Pernilla Andersson
- Center for Life-span Developmental Research (LEADER), School of Behavioral, Social and Legal Sciences, Örebro University, Fakultetsgatan 1, 702 81, Örebro, Sweden
| | - Xin Li
- Aging Research Center (ARC), Karolinska Institute and Stockholm University, Tomtebodavägen 18a, 171 65, Solna, Sweden
- Computational Brain Imaging Group, National University of Singapore, 21 Lower Kent Ridge Rd, 119077, Singapore
| | - Jonas Persson
- Center for Life-span Developmental Research (LEADER), School of Behavioral, Social and Legal Sciences, Örebro University, Fakultetsgatan 1, 702 81, Örebro, Sweden
- Aging Research Center (ARC), Karolinska Institute and Stockholm University, Tomtebodavägen 18a, 171 65, Solna, Sweden
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Walters AS, Spruyt K, Ba DM, Gao X. A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep. Tremor Other Hyperkinet Mov (N Y) 2024; 14:21. [PMID: 38708125 PMCID: PMC11067967 DOI: 10.5334/tohm.824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 03/21/2024] [Indexed: 05/07/2024] Open
Abstract
In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. Highlights Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.
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Affiliation(s)
| | - Karen Spruyt
- UniversitéParis Cité, NeuroDiderot INSERM, France
| | - Djibril M. Ba
- Penn State College of Medicine, Department of Public Health Sciences, Hershey, PA, USA
| | - Xiang Gao
- School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China
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Kujala J, Ciumas C, Jung J, Bouvard S, Lecaignard F, Lothe A, Bouet R, Ryvlin P, Jerbi K. GABAergic inhibition shapes behavior and neural dynamics in human visual working memory. Cereb Cortex 2024; 34:bhad522. [PMID: 38186005 PMCID: PMC10839845 DOI: 10.1093/cercor/bhad522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 01/09/2024] Open
Abstract
Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.
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Affiliation(s)
- Jan Kujala
- Department of Psychology, University of Jyväskylä, PO Box 35, Jyvaskyla FI-40014, Finland
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
| | - Carolina Ciumas
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
- Institute for Child and Adolescent with Epilepsy (IDEE), Lyon F-69000, France
| | - Julien Jung
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
- Department of Epileptology and Functional Neurology, Lyon Neurological Hospital, Lyon F-69000, France
| | - Sandrine Bouvard
- Institute for Child and Adolescent with Epilepsy (IDEE), Lyon F-69000, France
- CERMEP Imaging Center, Bron F-69003, France
| | - Françoise Lecaignard
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
- CERMEP Imaging Center, Bron F-69003, France
| | - Amélie Lothe
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
| | - Romain Bouet
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
| | - Philippe Ryvlin
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
- Institute for Child and Adolescent with Epilepsy (IDEE), Lyon F-69000, France
- Department of Clinical Neurosciences, CHUV, Lausanne 1011, Switzerland
| | - Karim Jerbi
- Lyon Neuroscience Research Center, INSERM U1028 - CNRS UMR5292, Lyon F-69000, France
- Department of Psychology, University of Montreal, Montreal, Québec H3C 3J7, Canada
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Walters AS, Li Y, Koo BB, Ondo WG, Weinstock LB, Champion D, Afrin LB, Karroum EG, Bagai K, Spruyt K. Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome. Brain 2024; 147:26-38. [PMID: 37633259 PMCID: PMC10796165 DOI: 10.1093/brain/awad283] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 07/23/2023] [Accepted: 08/01/2023] [Indexed: 08/28/2023] Open
Abstract
Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, β-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is β-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.
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Affiliation(s)
- Arthur S Walters
- Sleep Division, Department of Neurology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yuqing Li
- Norman Fixel Institute for Neurological Diseases, Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Brian B Koo
- Sleep Medicine Laboratory, VA Connecticut Health Care System, West Haven, CT 06516, USA
- Yale Center for Restless Legs Syndrome, Yale School of Medicine, New Haven, CT 06520, USA
| | - William G Ondo
- Department of Neurology, Methodist Hospital, Weill Cornell Medical School, Houston, TX 77030, USA
| | - Leonard B Weinstock
- Department of Internal Medicine, Washington University School of Medicine, St.Louis, MO 63130, USA
| | - David Champion
- Sydney Children's Hospital, Department of Pain Medicine, Randwick, NSW 2031, Australia
| | - Lawrence B Afrin
- Hematology/Oncology, AIM Center for Personalized Medicine, Purchase, NY 10577, USA
| | - Elias G Karroum
- Department of Neurology and Rehabilitation Medicine, The George Washington University School of Medicine and Health Sciences, George Washington University, Washington, D.C. 20052, USA
| | - Kanika Bagai
- Sleep Division, Department of Neurology, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Karen Spruyt
- Université Paris Cité, NeuroDiderot Inserm, Paris 75019, France
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Wang X, Wang T, Fan X, Zhang Z, Wang Y, Li Z. A Molecular Toolbox of Positron Emission Tomography Tracers for General Anesthesia Mechanism Research. J Med Chem 2023; 66:6463-6497. [PMID: 37145921 DOI: 10.1021/acs.jmedchem.2c01965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
With appropriate radiotracers, positron emission tomography (PET) allows direct or indirect monitoring of the spatial and temporal distribution of anesthetics, neurotransmitters, and biomarkers, making it an indispensable tool for studying the general anesthesia mechanism. In this Perspective, PET tracers that have been recruited in general anesthesia research are introduced in the following order: 1) 11C/18F-labeled anesthetics, i.e., PET tracers made from inhaled and intravenous anesthetics; 2) PET tracers targeting anesthesia-related receptors, e.g., neurotransmitters and voltage-gated ion channels; and 3) PET tracers for studying anesthesia-related neurophysiological effects and neurotoxicity. The radiosynthesis, pharmacodynamics, and pharmacokinetics of the above PET tracers are mainly discussed to provide a practical molecular toolbox for radiochemists, anesthesiologists, and those who are interested in general anesthesia.
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Affiliation(s)
- Xiaoxiao Wang
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China
| | - Tao Wang
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China
| | - Xiaowei Fan
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China
| | - Zhao Zhang
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Yingwei Wang
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Zijing Li
- Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361102, China
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McGinnity CJ, Riaño Barros DA, Hinz R, Myers JF, Yaakub SN, Thyssen C, Heckemann RA, de Tisi J, Duncan JS, Sander JW, Lingford-Hughes A, Koepp MJ, Hammers A. Αlpha 5 subunit-containing GABA A receptors in temporal lobe epilepsy with normal MRI. Brain Commun 2021; 3:fcaa190. [PMID: 33501420 PMCID: PMC7811756 DOI: 10.1093/braincomms/fcaa190] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 09/06/2020] [Accepted: 09/24/2020] [Indexed: 01/08/2023] Open
Abstract
GABAA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [11C]flumazenil has revealed reductions in GABAA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [11C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [V F; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (V S; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of V F and V S measures from a single bolus injection of [11C]Ro15-4513. The epilepsy group had higher V S in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas (P < 0.004). This was associated with reduced V F:V S ratios within the same areas (P < 0.009). Comparisons of V S for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation -0.4 ± 1.0 versus 0.7 ± 0.3; P = 0.02). In individuals with epilepsy, hippocampal V S did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced V F in the hippocampal area, which was significant ipsilaterally (P = 0.03), as expected from [11C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.
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Affiliation(s)
- Colm J McGinnity
- Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK
- MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK
- King's College London & Guy's and St Thomas' PET Centre, School of Biomedical Engineering & Imaging Sciences, King’s College London, London SE1 7EH, UK
| | - Daniela A Riaño Barros
- Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK
- MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK
| | - Rainer Hinz
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester M20 3LJ, UK
| | - James F Myers
- Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK
| | - Siti N Yaakub
- King's College London & Guy's and St Thomas' PET Centre, School of Biomedical Engineering & Imaging Sciences, King’s College London, London SE1 7EH, UK
| | - Charlotte Thyssen
- Medical Image and Signal Processing (MEDISIP), Department of Electronics and Information Systems, Faculty of Engineering and Architecture, Ghent University, 9000 Ghent, Belgium
| | - Rolf A Heckemann
- Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden
| | - Jane de Tisi
- NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK, and Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK
| | - John S Duncan
- NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK, and Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK
| | - Josemir W Sander
- NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK, and Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK
- Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede 2103SW, The Netherlands
| | - Anne Lingford-Hughes
- Neuropsychopharmacology Unit, Centre for Psychiatry, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, UK
| | - Matthias J Koepp
- NIHR University College London Hospitals Biomedical Research Centre, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK, and Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK
| | - Alexander Hammers
- Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK
- MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK
- King's College London & Guy's and St Thomas' PET Centre, School of Biomedical Engineering & Imaging Sciences, King’s College London, London SE1 7EH, UK
- Neurodis Foundation, CERMEP, Imagerie du Vivant, 69003 Lyon, France
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Peris-Yague A, Kiemes A, Cash D, Cotel MC, Singh N, Vernon AC, Modinos G. Region-specific and dose-specific effects of chronic haloperidol exposure on [ 3H]-flumazenil and [ 3H]-Ro15-4513 GABA A receptor binding sites in the rat brain. Eur Neuropsychopharmacol 2020; 41:106-117. [PMID: 33153853 PMCID: PMC7731940 DOI: 10.1016/j.euroneuro.2020.10.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 09/02/2020] [Accepted: 10/16/2020] [Indexed: 11/02/2022]
Abstract
Postmortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed postmortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d=+1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABAAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.
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Affiliation(s)
- Alba Peris-Yague
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom
| | - Amanda Kiemes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespingy Park, London SE5 8AF, United Kingdom
| | - Diana Cash
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom
| | - Marie-Caroline Cotel
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London SE5 9RT, United Kingdom
| | - Nisha Singh
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom
| | - Anthony C Vernon
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, 5 Cutcombe Road, London SE5 9RT, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.
| | - Gemma Modinos
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, United Kingdom; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespingy Park, London SE5 8AF, United Kingdom; MRC Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.
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8
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Liu B, Wang Z, Lin L, Yang H, Gao F, Gong T, Edden RAE, Wang G. Brain GABA+ changes in primary hypothyroidism patients before and after levothyroxine treatment: A longitudinal magnetic resonance spectroscopy study. Neuroimage Clin 2020; 28:102473. [PMID: 33395967 PMCID: PMC7663215 DOI: 10.1016/j.nicl.2020.102473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 10/15/2020] [Accepted: 10/17/2020] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Increasing evidence indicates the involvement of the GABAergic system in the pathophysiology of hypothyroidism. We aimed to investigate longitudinal changes of brain GABA in primary hypothyroidism before and after levothyroxine (L-T4) treatment. MATERIAL AND METHODS In 18 patients with hypothyroidism, we used the MEGA-PRESS (Mescher-Garwood point-resolved spectroscopy) editing sequence to measure brain GABA levels from medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) at baseline and after 6-months of L-T4 treatment. Sex- and age-matched healthy controls (n = 18) were scanned at baseline. Thyroid function and neuropsychological tests were also performed. RESULTS GABA signals were successfully quantified from all participants with fitting errors lower than 15%. GABA signal was labeled as GABA+ due to contamination from co-edited macromoleculars and homocarnosine. In hypothyroid patients, mean GABA+ was significantly lower in the mPFC region compared with controls (p = 0.031), and the mPFC GABA+ measurements were significantly correlated with depressive symptoms and memory function (r = -0.558, p = 0.016; r = 0.522, p = 0.026, respectively). After adequate L-T4 treatment, the mPFC GABA+ in hypothyroid patients increased to normal level, along with relieved neuropsychological impairments. CONCLUSION The study suggested the decrease of GABA+ may be an important neurobiological factor in the pathophysiology of hypothyroidism. Treatment of L-T4 may reverse the abnormal GABA+ and hypothyroidism-induced neuropsychiatric impairments, indicating the action mode of L-T4 in adjunctive treatment of affective disorders.
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Affiliation(s)
- Bo Liu
- Department of Radiology, Qilu Hospital of Shandong University, Jinan, China
| | - Zhensong Wang
- Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Liangjie Lin
- MSC Clinical & Technical Solutions, Philips Healthcare, Beijing, China
| | - Huan Yang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Fei Gao
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, China
| | - Tao Gong
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, China
| | - Richard A E Edden
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; FM Kirby Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA
| | - Guangbin Wang
- Shandong Medical Imaging Research Institute, Shandong University, Jinan, China.
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Kaar SJ, Natesan S, McCutcheon R, Howes OD. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology 2019; 172:107704. [PMID: 31299229 DOI: 10.1016/j.neuropharm.2019.107704] [Citation(s) in RCA: 217] [Impact Index Per Article: 36.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/13/2019] [Accepted: 07/08/2019] [Indexed: 12/17/2022]
Abstract
Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
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Affiliation(s)
- Stephen J Kaar
- Department of Psychosis Studies, 5th Floor, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, PO63 De Crespigny Park, London, SE5 8AF, United Kingdom.
| | - Sridhar Natesan
- Department of Psychosis Studies, 5th Floor, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, PO63 De Crespigny Park, London, SE5 8AF, United Kingdom
| | - Robert McCutcheon
- Department of Psychosis Studies, 5th Floor, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, PO63 De Crespigny Park, London, SE5 8AF, United Kingdom
| | - Oliver D Howes
- Department of Psychosis Studies, 5th Floor, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, PO63 De Crespigny Park, London, SE5 8AF, United Kingdom.
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10
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Jafarian M, Modarres Mousavi SM, Alipour F, Aligholi H, Noorbakhsh F, Ghadipasha M, Gharehdaghi J, Kellinghaus C, Kovac S, Khaleghi Ghadiri M, Meuth SG, Speckmann EJ, Stummer W, Gorji A. Cell injury and receptor expression in the epileptic human amygdala. Neurobiol Dis 2019; 124:416-427. [DOI: 10.1016/j.nbd.2018.12.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 12/04/2018] [Accepted: 12/22/2018] [Indexed: 02/06/2023] Open
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Møller A, Rømer Thomsen K, Brooks DJ, Mouridsen K, Blicher JU, Hansen KV, Lou HC. Attenuation of dopamine-induced GABA release in problem gamblers. Brain Behav 2019; 9:e01239. [PMID: 30788911 PMCID: PMC6422713 DOI: 10.1002/brb3.1239] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 01/17/2019] [Accepted: 01/18/2019] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.
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Affiliation(s)
- Arne Møller
- Nuclear Medicine and PET-Center, Aarhus University Hospital, Aarhus, Denmark.,Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
| | | | - David J Brooks
- Nuclear Medicine and PET-Center, Aarhus University Hospital, Aarhus, Denmark.,Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark.,Division of Neuroscience, University of Newcastle, Tyne, UK
| | - Kim Mouridsen
- Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
| | - Jakob U Blicher
- Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
| | - Kim V Hansen
- Nuclear Medicine and PET-Center, Aarhus University Hospital, Aarhus, Denmark
| | - Hans C Lou
- Center of Functionally Integrative Neuroscience, Aarhus University, Aarhus, Denmark
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Andersson JD, Matuskey D, Finnema SJ. Positron emission tomography imaging of the γ-aminobutyric acid system. Neurosci Lett 2018; 691:35-43. [PMID: 30102960 DOI: 10.1016/j.neulet.2018.08.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/06/2018] [Accepted: 08/09/2018] [Indexed: 01/08/2023]
Abstract
In this review, we summarize the recent development of positron emission tomography (PET) radioligands for γ-aminobutyric acid A (GABAA) receptors and their potential to measure changes in endogenous GABA levels and highlight the clinical and translational applications of GABA-sensitive PET radioligands. We review the basic physiology of the GABA system with a focus on the importance of GABAA receptors in the brain and specifically the benzodiazepine binding site. Challenges for the development of central nervous system radioligands and particularly for radioligands with increased GABA sensitivity are outlined, as well as the status of established benzodiazepine site PET radioligands and agonist GABAA radioligands. We underline the challenge of using allosteric interactions to measure GABA concentrations and review the current state of PET imaging of changes in GABA levels. We conclude that PET tracers with increased GABA sensitivity are required to efficiently measure GABA release and that such a tool could be broadly applied to assess GABA transmission in vivo across several disorders.
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Affiliation(s)
- Jan D Andersson
- University of Alberta, Medical Isotope and Cyclotron Facility, Edmonton, Canada
| | - David Matuskey
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA
| | - Sjoerd J Finnema
- PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA; Center for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Dupont AC, Largeau B, Guilloteau D, Santiago Ribeiro MJ, Arlicot N. The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:7043578. [PMID: 29887768 PMCID: PMC5985069 DOI: 10.1155/2018/7043578] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 04/01/2018] [Indexed: 12/16/2022]
Abstract
In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.
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Affiliation(s)
- Anne-Claire Dupont
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- CHRU de Tours, Unité de Radiopharmacie, Tours, France
| | | | - Denis Guilloteau
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- CHRU de Tours, Service de Médecine Nucléaire in vitro, Tours, France
- INSERM CIC 1415, University Hospital, Tours, France
| | - Maria Joao Santiago Ribeiro
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- INSERM CIC 1415, University Hospital, Tours, France
- CHRU de Tours, Service de Médecine Nucléaire in vivo, Tours, France
| | - Nicolas Arlicot
- UMR 1253, iBrain, Université de Tours, Inserm, Tours, France
- CHRU de Tours, Unité de Radiopharmacie, Tours, France
- INSERM CIC 1415, University Hospital, Tours, France
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Bertelsen F, Landau AM, Vase KH, Jacobsen J, Scheel-Krüger J, Møller A. Acute in vivo effect of valproic acid on the GABAergic system in rat brain: A [ 11C]Ro15-4513 microPET study. Brain Res 2017; 1680:110-114. [PMID: 29258847 DOI: 10.1016/j.brainres.2017.12.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/08/2017] [Accepted: 12/13/2017] [Indexed: 02/05/2023]
Abstract
γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system acting mainly through GABAA receptors. In the presence of high levels of GABA, an allosteric shift in the GABAA receptors can change the affinity of benzodiazepine (BZD) ligands. Valproic acid (VPA) is an anticonvulsant that enhances the level of endogenous GABA in the brain. The BZD ligand, Ro15-4513 has a high affinity for GABAA receptors containing the α5 subunit and can be used to investigate the GABA shift in the brains of living rats after VPA exposure. Seven Wistar rats were scanned using a Mediso NanoScan PET/MRI. A baseline 90-min dynamic [11C]Ro15-4513 PET scan was acquired prior to an intravenous injection of 50 mg/kg VPA, and was followed by a second [11C]Ro15-4513 PET scan. Standardized uptake values were obtained for regions of high GABA binding, including the hippocampus and amygdala, and low GABA binding such as the cerebellum. We showed a significant increase in [11C]Ro15-4513 uptake in hippocampus and amygdala, but no significant differences in cerebellar uptake, after acute VPA exposure. In contrast to several in vitro studies, we demonstrated a positive allosteric change in the GABAA receptors after pharmacologically enhanced GABA levels resulting in enhanced Ro15-4513 uptake. Knowledge of how subtypes of the GABAA receptors react will provide us with information useful to fine-tune pharmacological interventions and design receptor subtype specific drugs.
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Affiliation(s)
- Freja Bertelsen
- Centre of Functionally Integrative Neuroscience, Aarhus University, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark; Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark.
| | - Anne M Landau
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark; Translational Neuropsychiatry Unit, Aarhus University, Skovagervej 2, Building 14J.1, 8240 Risskov, Denmark.
| | - Karina H Vase
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark.
| | - Jan Jacobsen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark.
| | - Jørgen Scheel-Krüger
- Centre of Functionally Integrative Neuroscience, Aarhus University, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark.
| | - Arne Møller
- Centre of Functionally Integrative Neuroscience, Aarhus University, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark; Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Nørrebrogade 44, Building 10G, 8000 Aarhus, Denmark.
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Sander CY, Hesse S. News and views on in-vivo imaging of neurotransmission using PET and MRI. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF... 2017; 61:414-428. [PMID: 28750497 PMCID: PMC5916779 DOI: 10.23736/s1824-4785.17.03019-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Molecular neuroimaging with PET is an integrated tool in psychiatry research and drug-development for as long as this modality has been available, in particular for studying neurotransmission and endogenous neurotransmitter release. Pharmacologic, behavioral and other types of challenges are currently applied to induce changes in neurochemical levels that can be inferred through their effects on changes in receptor binding and related outcome measures. Based on the availability of tracers that are sensitive for measuring neurotransmitter release these experiments have focused on the brain's dopamine system, while recent developments have extended those studies to other targets such as the serotonin or choline system. With the introduction of hybrid, truly simultaneous PET/MRI systems, in-vivo imaging of the dynamics of neuroreceptor signal transmission in the brain using PET and functional MRI (fMRI) has become possible. fMRI has the ability to provide information about the effects of receptor function that are complementary to the PET measurement. Dynamic acquisition of both PET and fMRI signals enables not only an in-vivo real-time assessment of neurotransmitter or drug binding to receptors but also dynamic receptor adaptations and receptor-specific neurotransmission. While fMRI temporal resolution is comparatively fast in relation to PET, the timescale of observable biological processes is highly dependent on the kinetics of radiotracers and study design. Overall, the combination of the specificity of PET radiotracers to neuroreceptors, fMRI signal as a functional readout and integrated study design promises to expand our understanding of the location, propagation and connections of brain activity in health and disease.
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Affiliation(s)
- Christin Y Sander
- Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA -
- Harvard Medical School, Boston, MA, USA -
| | - Swen Hesse
- Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany
- Integrated Treatment and Research Center (IFB) Adiposity Diseases, Leipzig University Medical Center, Leipzig, Germany
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Mick I, Ramos AC, Myers J, Stokes PR, Chandrasekera S, Erritzoe D, Mendez MA, Gunn RN, Rabiner EA, Searle GE, Galduróz JCF, Waldman AD, Bowden-Jones H, Clark L, Nutt DJ, Lingford-Hughes AR. Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity. Addict Biol 2017; 22:1601-1609. [PMID: 27739164 PMCID: PMC5697606 DOI: 10.1111/adb.12457] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 07/14/2016] [Accepted: 08/30/2016] [Indexed: 12/11/2022]
Abstract
As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15‐4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
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Affiliation(s)
- Inge Mick
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Anna C. Ramos
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Department of Psychobiology; Universidade Federal de São Paulo; Brazil
| | - Jim Myers
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Paul R. Stokes
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Centre for Affective Disorders, Department of Psychological Medicine; Institute of Psychiatry, Psychology and Neuroscience, King's College London; UK
| | - Samantha Chandrasekera
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - David Erritzoe
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Maria A. Mendez
- Forensic and Neurodevelopmental Sciences; Institute of Psychiatry, King's College; UK
| | - Roger N. Gunn
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
- Imanova Ltd.; Centre for Imaging Sciences; UK
| | - Eugenii A. Rabiner
- Imanova Ltd.; Centre for Imaging Sciences; UK
- Department of Neuroimaging; Institute of Psychiatry, King's College; UK
| | | | | | - Adam D. Waldman
- Department of Imaging, Division of Experimental Medicine, Department of Medicine; Imperial College; UK
| | - Henrietta Bowden-Jones
- National Problem Gambling Clinic, CNWL NHS Foundation Trust; Imperial College London; UK
| | - Luke Clark
- Centre for Gambling Research at UBC, Department of Psychology; University of British Columbia; Canada
| | - David J. Nutt
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
| | - Anne R. Lingford-Hughes
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Faculty of Medicine; Imperial College London; UK
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Lord LD, Stevner AB, Deco G, Kringelbach ML. Understanding principles of integration and segregation using whole-brain computational connectomics: implications for neuropsychiatric disorders. PHILOSOPHICAL TRANSACTIONS. SERIES A, MATHEMATICAL, PHYSICAL, AND ENGINEERING SCIENCES 2017; 375:rsta.2016.0283. [PMID: 28507228 PMCID: PMC5434074 DOI: 10.1098/rsta.2016.0283] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/05/2016] [Indexed: 05/18/2023]
Abstract
To survive in an ever-changing environment, the brain must seamlessly integrate a rich stream of incoming information into coherent internal representations that can then be used to efficiently plan for action. The brain must, however, balance its ability to integrate information from various sources with a complementary capacity to segregate information into modules which perform specialized computations in local circuits. Importantly, evidence suggests that imbalances in the brain's ability to bind together and/or segregate information over both space and time is a common feature of several neuropsychiatric disorders. Most studies have, however, until recently strictly attempted to characterize the principles of integration and segregation in static (i.e. time-invariant) representations of human brain networks, hence disregarding the complex spatio-temporal nature of these processes. In the present Review, we describe how the emerging discipline of whole-brain computational connectomics may be used to study the causal mechanisms of the integration and segregation of information on behaviourally relevant timescales. We emphasize how novel methods from network science and whole-brain computational modelling can expand beyond traditional neuroimaging paradigms and help to uncover the neurobiological determinants of the abnormal integration and segregation of information in neuropsychiatric disorders.This article is part of the themed issue 'Mathematical methods in medicine: neuroscience, cardiology and pathology'.
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Affiliation(s)
| | - Angus B Stevner
- Department of Psychiatry, University of Oxford, Oxford, UK
- Center for Music in the Brain, Aarhus University, Aarhus, Denmark
| | - Gustavo Deco
- Center for Brain and Cognition, Universitat Pompeu Fabra, Barcelona, Spain
- Instituci Catalana de la Recerca i Estudis Avanats (ICREA), Universitat Pompeu Fabra, Barcelona, Spain
- Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
- School of Psychological Sciences, Monash University, Melbourne, Australia, Clayton VIC 3800
| | - Morten L Kringelbach
- Department of Psychiatry, University of Oxford, Oxford, UK
- Center for Music in the Brain, Aarhus University, Aarhus, Denmark
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Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis. Transl Psychiatry 2017; 7:e1147. [PMID: 28585933 PMCID: PMC5537645 DOI: 10.1038/tp.2017.124] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 04/26/2017] [Accepted: 05/03/2017] [Indexed: 01/17/2023] Open
Abstract
Data from animal models and from postmortem studies suggest that schizophrenia is associated with brain GABAergic dysfunction. The extent to which this is reflected in data from in vivo studies of GABA function in schizophrenia is unclear. The Medline database was searched to identify articles published until 21 October 2016. The search terms included GABA, proton magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), single photon emission computed tomography (SPECT), schizophrenia and psychosis. Sixteen GABA 1H-MRS studies (538 controls, 526 patients) and seven PET/SPECT studies of GABAA/benzodiazepine receptor (GABAA/BZR) availability (118 controls, 113 patients) were identified. Meta-analyses of 1H-MRS GABA in the medial prefrontal cortex (mPFC), parietal/occipital cortex (POC) and striatum did not show significant group differences (mFC: g=-0.3, 409 patients, 495 controls, 95% confidence interval (CI): -0.6 to 0.1; POC: g=-0.3, 139 patients, 111 controls, 95% CI: -0.9 to 0.3; striatum: g=-0.004, 123 patients, 95 controls, 95% CI: -0.7 to 0.7). Heterogeneity across studies was high (I2>50%), and this was not explained by subsequent moderator or meta-regression analyses. There were insufficient PET/SPECT receptor availability studies for meta-analyses, but a systematic review did not suggest replicable group differences in regional GABAA/BZR availability. The current literature does not reveal consistent alterations in in vivo GABA neuroimaging measures in schizophrenia, as might be hypothesized from animal models and postmortem data. The analysis highlights the need for further GABA neuroimaging studies with improved methodology and addressing potential sources of heterogeneity.
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McGinnity CJ, Riaño Barros DA, Rosso L, Veronese M, Rizzo G, Bertoldo A, Hinz R, Turkheimer FE, Koepp MJ, Hammers A. Test-retest reproducibility of quantitative binding measures of [ 11C]Ro15-4513, a PET ligand for GABA A receptors containing alpha5 subunits. Neuroimage 2017; 152:270-282. [PMID: 28292717 PMCID: PMC5440177 DOI: 10.1016/j.neuroimage.2016.12.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Revised: 11/20/2016] [Accepted: 12/14/2016] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Alteration of γ-aminobutyric acid "A" (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants). METHODS Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus. RESULTS Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum. CONCLUSION Quantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.
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Affiliation(s)
- Colm J McGinnity
- Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK; Division of Imaging Sciences & Biomedical Engineering, King's College London, London, UK.
| | - Daniela A Riaño Barros
- Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK
| | - Lula Rosso
- Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK
| | - Mattia Veronese
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Gaia Rizzo
- Department of Information Engineering, University of Padova, Padova, Italy
| | | | - Rainer Hinz
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK
| | - Federico E Turkheimer
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Matthias J Koepp
- Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK; Epilepsy Society, Chalfont St Peter, UK
| | - Alexander Hammers
- Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK; Division of Imaging Sciences & Biomedical Engineering, King's College London, London, UK; The Neurodis Foundation, CERMEP - Imagerie du Vivant, Lyon, France
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20
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Kassenbrock A, Vasdev N, Liang SH. Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors. Curr Top Med Chem 2017; 16:1830-42. [PMID: 26975506 DOI: 10.2174/1568026616666160315142457] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 08/01/2015] [Accepted: 08/03/2015] [Indexed: 12/11/2022]
Abstract
Positron emission tomography (PET) neuroimaging of ion channel linked receptors is a developing area of preclinical and clinical research. The present review focuses on recent advances with radiochemistry, preclinical and clinical PET imaging studies of three receptors that are actively pursued in neuropsychiatric drug discovery: namely the γ-aminobutyric acid-benzodiazapine (GABA) receptor, nicotinic acetylcholine receptor (nAChR), and N-methyl-D-aspartate (NMDA) receptor. Recent efforts to develop new PET radioligands for these targets with improved brain uptake, selectivity, stability and pharmacokinetics are highlighted.
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Affiliation(s)
| | | | - Steven H Liang
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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21
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Volkow ND, Wiers CE, Shokri-Kojori E, Tomasi D, Wang GJ, Baler R. Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: Studies with positron emission tomography. Neuropharmacology 2017; 122:175-188. [PMID: 28108358 DOI: 10.1016/j.neuropharm.2017.01.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 12/20/2016] [Accepted: 01/14/2017] [Indexed: 02/07/2023]
Abstract
The use of Positron emission tomography (PET) to study the effects of acute and chronic alcohol on the human brain has enhanced our understanding of the mechanisms underlying alcohol's rewarding effects, the neuroadaptations from chronic exposure that contribute to tolerance and withdrawal, and the changes in fronto-striatal circuits that lead to loss of control and enhanced motivation to drink that characterize alcohol use disorders (AUD). These include studies showing that alcohol's reinforcing effects may result not only from its enhancement of dopaminergic, GABAergic and opioid signaling but also from its caloric properties. Studies in those suffering from an AUD have revealed significant alterations in dopamine (DA), GABA, cannabinoids, opioid and serotonin neurotransmission and in brain energy utilization (glucose and acetate metabolism) that are likely to contribute to compulsive alcohol taking, dysphoria/depression, and to alcohol-associated neurotoxicity. Studies have also evaluated the effects of abstinence on recovery of brain metabolism and neurotransmitter function and the potential value of some of these measures to predict clinical outcomes. Finally, PET studies have started to provide insights about the neuronal mechanisms by which certain genes contribute to the vulnerability to AUD. These findings have helped identify new strategies for prevention and treatment of AUD. This article is part of the Special Issue entitled "Alcoholism".
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Affiliation(s)
- Nora D Volkow
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, United States; National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, National Institutes of Health, Bethesda, MD 20892, United States.
| | - Corinde E Wiers
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, United States
| | - Ehsan Shokri-Kojori
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, United States
| | - Dardo Tomasi
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, United States
| | - Gene-Jack Wang
- National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, United States
| | - Ruben Baler
- National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, National Institutes of Health, Bethesda, MD 20892, United States
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22
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PET measurement of "GABA shift" in the rat brain: A preclinical application of bolus plus constant infusion paradigm of [ 18F]flumazenil. Nucl Med Biol 2016; 45:30-34. [PMID: 27886620 DOI: 10.1016/j.nucmedbio.2016.11.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/22/2016] [Accepted: 11/01/2016] [Indexed: 11/21/2022]
Abstract
INTRODUCTION We measured the tiagabine-induced enhancement of the GABAA receptor's affinity for benzodiazepine ligands ("GABA shift") using [18F]flumazenil (FMZ) PET with preclinical application of bolus plus constant infusion (B/I). Differences in quantified results of [18F]FMZ binding were compared to that of [18F]FMZ PET with single bolus injection (SB). MATERIALS AND METHODS Sprague-Dawley rats underwent [18F]FMZ PET scans with B/I, which consisted of baseline and "GABA shift" sessions in a scan, or scans with SB one week apart. Tiagabine (10mg/kg) was intravenously injected after the baseline session. [18F]FMZ binding potentials (BPND) were calculated using an equilibrium ratio method and a modeling method for B/I and SB, respectively. Regional brain BPND changes (%) before and after the tiagabine treatment were also calculated. RESULTS In PET studies with B/I (Kbol=20min), [18F]FMZ distribution in the various cortical and subcortical regions rapidly reached equilibrium. After the tiagabine treatment, [18F]FMZ BPND were substantially increased across the regions of interest (the frontal cortex, hippocampus, thalamus, and striatum), ranging from 3% to 7% BPND change (B/I) and 6-14% BPND change (SB), respectively. In PET studies with SB, a statistically significant increase of [18F]FMZ BPND was found only in the striatum, due to the greater inter-individual variance compared to those with B/I. CONCLUSIONS Data demonstrated that an [18F]FMZ PET study with B/I (Kbol=20min) is both reliable and sensitive for the assessment of altered GABAA receptor function induced by tiagabine treatment in the rat brain. These results may help to improve the efficiency of the development of new GABA-targeting drugs in the preclinical stage using [18F]FMZ PET.
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23
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Lou HC, Rosenstand A, Brooks DJ, Bender D, Jakobsen S, Blicher JU, Hansen KV, Møller A. Exogenous dopamine reduces GABA receptor availability in the human brain. Brain Behav 2016; 6:e00484. [PMID: 27247854 PMCID: PMC4864053 DOI: 10.1002/brb3.484] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 03/10/2016] [Accepted: 03/24/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND While it has recently been shown that dopamine release stimulates conscious self-monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. METHODS Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [(11)C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. RESULTS We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [(11)C] Ro15-4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.
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Affiliation(s)
- Hans C Lou
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Astrid Rosenstand
- Dept. Ophtalmology Rigshospitalet Glostrup Copenhagen University Denmark
| | - David J Brooks
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Dirk Bender
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Steen Jakobsen
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Jakob U Blicher
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Kim V Hansen
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
| | - Arne Møller
- CFIN and Pet Center Aarhus University Norregade 44 8000 Aarhus Denmark
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24
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Myers JF, Nutt DJ, Lingford-Hughes AR. γ-aminobutyric acid as a metabolite: Interpreting magnetic resonance spectroscopy experiments. J Psychopharmacol 2016; 30:422-7. [PMID: 27005308 DOI: 10.1177/0269881116639298] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The current rise in the prevalence of magnetic resonance spectroscopy experiments to measure γ-aminobutyric acid in the living human brain is an exciting and productive area of research. As research spreads into clinical populations and cognitive research, it is important to fully understand the source of the magnetic resonance spectroscopy signal and apply appropriate interpretation to the results of the experiments. γ-aminobutyric acid is present in the brain not only as a neurotransmitter, but also in high intracellular concentrations, both as a transmitter precursor and a metabolite. γ-aminobutyric acid concentrations measured by magnetic resonance spectroscopy are not necessarily implicated in neurotransmission and therefore may reflect a very different brain activity to that commonly suggested. In this perspective, we examine some of the considerations to be taken in the interpretation of any γ-aminobutyric acid signal measured by magnetic resonance spectroscopy.
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Affiliation(s)
- James Fm Myers
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK
| | - David J Nutt
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK
| | - Anne R Lingford-Hughes
- Centre for Neuropsychopharmacology, Division of Brain Sciences, Imperial College London, London, UK
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25
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Goddard AW. Cortical and subcortical gamma amino acid butyric acid deficits in anxiety and stress disorders: Clinical implications. World J Psychiatry 2016; 6:43-53. [PMID: 27014597 PMCID: PMC4804267 DOI: 10.5498/wjp.v6.i1.43] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 12/18/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Anxiety and stress disorders are a major public health issue. However, their pathophysiology is still unclear. The gamma amino acid butyric acid (GABA) neurochemical system has been strongly implicated in their pathogenesis and treatment by numerous preclinical and clinical studies, the most recent of which have been highlighted and critical review in this paper. Changes in cortical GABA appear related to normal personality styles and responses to stress. While there is accumulating animal and human neuroimaging evidence of cortical and subcortical GABA deficits across a number of anxiety conditions, a clear pattern of findings in specific brain regions for a given disorder is yet to emerge. Neuropsychiatric conditions with anxiety as a clinical feature may have GABA deficits as an underlying feature. Different classes of anxiolytic therapies support GABA function, and this may be an area in which newer GABA neuroimaging techniques could soon offer more personalized therapy. Novel GABAergic pharmacotherapies in development offer potential improvements over current therapies in reducing sedative and physiologic dependency effects, while offering rapid anxiolysis.
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26
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Lingford-Hughes A, Myers J, Watson B, Reid AG, Kalk N, Feeney A, Hammers A, Riaño-Barros DA, McGinnity CJ, Taylor LG, Rosso L, Brooks DJ, Turkheimer F, Nutt DJ. Using [(11)C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism. Neuroimage 2016; 132:1-7. [PMID: 26876472 PMCID: PMC4862962 DOI: 10.1016/j.neuroimage.2016.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Revised: 01/31/2016] [Accepted: 02/04/2016] [Indexed: 01/19/2023] Open
Abstract
The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised in addiction. Using the α1/α5 benzodiazepine receptor PET radioligand [11C]Ro15 4513, we previously showed reduced binding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that reduced [11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampus and positive relationship with memory was a consequence of chronic alcohol abuse. To examine this further we assessed [11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysis to estimate contributions of α1 and α5 subtypes to [11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependent groups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [11C]Ro15 4513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy control group. There was no relationship between [11C]Ro15 4513 binding in the hippocampus with memory. We found that reduced [11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependent group. This was also seen in an alcohol-dependent group where an association between memory performance and [11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reduced α5 levels in the nucleus accumbens are associated with addiction since we have now shown this in dependence to two pharmacologically different substances, alcohol and opiates.
Lower [11C]Ro15 4513 binding is evident in the nucleus accumbens of opiate addicts. This appears primarily due to lower levels of α5 subtype of the GABA-A receptor. Lower [11C]Ro15 4513 binding is similarly found in alcoholism. Lower levels of α5 GABA-A receptor in nucleus accumbens may underpin addiction.
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Affiliation(s)
- Anne Lingford-Hughes
- Centre for Neuropsychopharmacology, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom; Hammersmith Imanet Ltd., Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom.
| | - James Myers
- Centre for Neuropsychopharmacology, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Ben Watson
- Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom; Hammersmith Imanet Ltd., Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom
| | - Alastair G Reid
- Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom; Hammersmith Imanet Ltd., Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom
| | - Nicola Kalk
- Centre for Neuropsychopharmacology, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Adrian Feeney
- Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Alexander Hammers
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Daniela A Riaño-Barros
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Colm J McGinnity
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - Lindsay G Taylor
- Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom
| | - Lula Rosso
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - David J Brooks
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom; Hammersmith Imanet Ltd., Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom
| | - Federico Turkheimer
- MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
| | - David J Nutt
- Centre for Neuropsychopharmacology, Imperial College London, Du Cane Rd., London W12 0NN, United Kingdom; Psychopharmacology Unit, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom; MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom
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27
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Veronese M, Zanotti-Fregonara P, Rizzo G, Bertoldo A, Innis RB, Turkheimer FE. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot. Neuroimage 2016; 130:1-12. [PMID: 26850512 DOI: 10.1016/j.neuroimage.2016.01.058] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 01/26/2016] [Indexed: 12/11/2022] Open
Abstract
PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.
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Affiliation(s)
- Mattia Veronese
- Department of Neuroimaging, IoPPN, King's College London, London, UK
| | - Paolo Zanotti-Fregonara
- Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA; INCIA UMR-CNRS 5287, Université de Bordeaux, Bordeaux, France
| | - Gaia Rizzo
- Department of Information Engineering, University of Padova, Padova, Italy
| | | | - Robert B Innis
- Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA
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28
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Moeller SJ, London ED, Northoff G. Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity. Neurosci Biobehav Rev 2016; 61:35-52. [PMID: 26657968 PMCID: PMC4731270 DOI: 10.1016/j.neubiorev.2015.11.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 11/05/2015] [Accepted: 11/21/2015] [Indexed: 12/29/2022]
Abstract
Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications.
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Affiliation(s)
- Scott J Moeller
- Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Edythe D London
- Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Departments of Psychiatry and Biobehavioral Sciences, and Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
| | - Georg Northoff
- Brain Imaging and Neuroethics Research Unit, Institute of Mental Health Research, Ottawa, Canada.
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29
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Lehto J, Scheinin A, Johansson J, Marjamäki P, Arponen E, Scheinin H, Scheinin M. Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070. Synapse 2015; 70:57-65. [DOI: 10.1002/syn.21872] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/21/2015] [Accepted: 11/01/2015] [Indexed: 11/11/2022]
Affiliation(s)
- Jussi Lehto
- Department of Pharmacology; Drug Development and Therapeutics, University of Turku; Turku Finland
- Clinical Research Services Turku CRST; Turku Finland
- Unit of Clinical Pharmacology, Turku University Hospital; Turku Finland
| | - Annalotta Scheinin
- Turku PET Centre; University of Turku, Turku University Hospital; Turku Finland
| | - Jarkko Johansson
- Turku PET Centre; University of Turku, Turku University Hospital; Turku Finland
| | - Päivi Marjamäki
- Turku PET Centre; University of Turku, Turku University Hospital; Turku Finland
| | - Eveliina Arponen
- Turku PET Centre; University of Turku, Turku University Hospital; Turku Finland
| | - Harry Scheinin
- Department of Pharmacology; Drug Development and Therapeutics, University of Turku; Turku Finland
- Turku PET Centre; University of Turku, Turku University Hospital; Turku Finland
| | - Mika Scheinin
- Department of Pharmacology; Drug Development and Therapeutics, University of Turku; Turku Finland
- Clinical Research Services Turku CRST; Turku Finland
- Unit of Clinical Pharmacology, Turku University Hospital; Turku Finland
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30
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Kujala J, Jung J, Bouvard S, Lecaignard F, Lothe A, Bouet R, Ciumas C, Ryvlin P, Jerbi K. Gamma oscillations in V1 are correlated with GABA(A) receptor density: A multi-modal MEG and Flumazenil-PET study. Sci Rep 2015; 5:16347. [PMID: 26572733 PMCID: PMC4647220 DOI: 10.1038/srep16347] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/12/2015] [Indexed: 12/02/2022] Open
Abstract
High-frequency oscillations in the gamma-band reflect rhythmic synchronization of spike timing in active neural networks. The modulation of gamma oscillations is a widely established mechanism in a variety of neurobiological processes, yet its neurochemical basis is not fully understood. Modeling, in-vitro and in-vivo animal studies suggest that gamma oscillation properties depend on GABAergic inhibition. In humans, search for evidence linking total GABA concentration to gamma oscillations has led to promising -but also to partly diverging- observations. Here, we provide the first evidence of a direct relationship between the density of GABAA receptors and gamma oscillatory gamma responses in human primary visual cortex (V1). By combining Flumazenil-PET (to measure resting-levels of GABAA receptor density) and MEG (to measure visually-induced gamma oscillations), we found that GABAA receptor densities correlated positively with the frequency and negatively with amplitude of visually-induced gamma oscillations in V1. Our findings demonstrate that gamma-band response profiles of primary visual cortex across healthy individuals are shaped by GABAA-receptor-mediated inhibitory neurotransmission. These results bridge the gap with in-vitro and animal studies and may have future clinical implications given that altered GABAergic function, including dysregulation of GABAA receptors, has been related to psychiatric disorders including schizophrenia and depression.
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Affiliation(s)
- Jan Kujala
- Department of Neuroscience and Biomedical Engineering, Aalto University, 02150 Espoo, Finland.,Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France
| | - Julien Jung
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France.,Department of Epileptology and Functional Neurology, Lyon Neurological Hospital, F-69000, Lyon, France
| | - Sandrine Bouvard
- CERMEP imaging center, F-69003, Bron, France.,Institute for Child and Adolescent with Epilepsy (IDEE), F-69000, Lyon, France
| | - Françoise Lecaignard
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France.,CERMEP imaging center, F-69003, Bron, France
| | - Amélie Lothe
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France
| | - Romain Bouet
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France
| | - Carolina Ciumas
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France.,Institute for Child and Adolescent with Epilepsy (IDEE), F-69000, Lyon, France
| | - Philippe Ryvlin
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France.,Institute for Child and Adolescent with Epilepsy (IDEE), F-69000, Lyon, France.,Department of Clinical Neurosciences, CHUV, 1011, Lausanne, Switzerland
| | - Karim Jerbi
- Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, F-69000, Lyon, France.,Department of Psychology, University of Montreal, H3C 3J7 Montreal, Québec, Canada
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Yilmazer-Hanke D, O'Loughlin E, McDermott K. Contribution of amygdala pathology to comorbid emotional disturbances in temporal lobe epilepsy. J Neurosci Res 2015; 94:486-503. [DOI: 10.1002/jnr.23689] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 10/07/2015] [Accepted: 10/16/2015] [Indexed: 12/19/2022]
Affiliation(s)
- Deniz Yilmazer-Hanke
- Department of Biomedical Sciences, School of Medicine; Creighton University; Omaha Nebraska
- Department of Anatomy and Neuroscience; University College; Cork Ireland
| | - Elaine O'Loughlin
- Department of Anatomy and Neuroscience; University College; Cork Ireland
- Ann Romney Centre for Neurologic Diseases, Brigham and Women's Hospital; Harvard Medical School; Boston Massachusetts
| | - Kieran McDermott
- Department of Anatomy and Neuroscience; University College; Cork Ireland
- Graduate Entry Medical School; University of Limerick; Limerick Ireland
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Frankle WG, Cho RY, Prasad KM, Mason NS, Paris J, Himes ML, Walker C, Lewis DA, Narendran R. In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients. Am J Psychiatry 2015; 172:1148-59. [PMID: 26133962 PMCID: PMC5070491 DOI: 10.1176/appi.ajp.2015.14081031] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. METHOD The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). RESULTS [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. CONCLUSIONS This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.
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GABA abnormalities in schizophrenia: a methodological review of in vivo studies. Schizophr Res 2015; 167:84-90. [PMID: 25458856 PMCID: PMC4409914 DOI: 10.1016/j.schres.2014.10.011] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 10/04/2014] [Accepted: 10/07/2014] [Indexed: 12/31/2022]
Abstract
Abnormalities of GABAergic interneurons are some of the most consistent findings from post-mortem studies of schizophrenia. However, linking these molecular deficits with in vivo observations in patients - a critical goal in order to evaluate interventions that would target GABAergic deficits - presents a challenge. Explanatory models have been developed based on animal work and the emerging experimental literature in schizophrenia patients. This literature includes: neuroimaging ligands to GABA receptors, magnetic resonance spectroscopy (MRS) of GABA concentration, transcranial magnetic stimulation of cortical inhibitory circuits and pharmacologic probes of GABA receptors to dynamically challenge the GABA system, usually in combination with neuroimaging studies. Pharmacologic challenges have elicited behavioral changes, and preliminary studies of therapeutic GABAergic interventions have been conducted. This article critically reviews the evidence for GABAergic dysfunction from each of these areas. These methods remain indirect measures of GABAergic function, and a broad array of dysfunction is linked with the putative GABAergic measures, including positive symptoms, cognition, emotion, motor processing and sensory processing, covering diverse brain areas. Measures of receptor binding have not shown replicable group differences in binding, and MRS assays of GABA concentration have yielded equivocal evidence of large-scale alteration in GABA concentration. Overall, the experimental base remains sparse, and much remains to be learned about the role of GABAergic interneurons in healthy brains. Challenges with pharmacologic and functional probes show promise, and may yet enable a better characterization of GABAergic deficits in schizophrenia.
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Optimising PET approaches to measuring 5-HT release in human brain. Synapse 2015; 69:505-11. [DOI: 10.1002/syn.21835] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 05/28/2015] [Accepted: 06/08/2015] [Indexed: 01/16/2023]
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Tse MT, Piantadosi PT, Floresco SB. Prefrontal cortical gamma-aminobutyric acid transmission and cognitive function: drawing links to schizophrenia from preclinical research. Biol Psychiatry 2015; 77:929-39. [PMID: 25442792 DOI: 10.1016/j.biopsych.2014.09.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 08/22/2014] [Accepted: 09/15/2014] [Indexed: 12/28/2022]
Abstract
Cognitive dysfunction in schizophrenia is one of the most pervasive and debilitating aspects of the disorder. Among the numerous neural abnormalities that may contribute to schizophrenia symptoms, perturbations in markers for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), particularly within the frontal lobes, are some of the most reliable alterations observed at postmortem examination. However, how prefrontal GABA dysfunction contributes to cognitive impairment in schizophrenia remains unclear. We provide an overview of postmortem GABAergic perturbations in the brain affected by schizophrenia and describe circumstantial evidence linking these alterations to cognitive dysfunction. In addition, we conduct a survey of studies using neurodevelopmental, genetic, and pharmacologic rodent models that induce schizophrenia-like cognitive impairments, highlighting the convergence of these mechanistically distinct approaches to prefrontal GABAergic disruption. We review preclinical studies that have directly targeted prefrontal cortical GABAergic transmission using local application of GABAA receptor antagonists. These studies have provided an important link between GABA transmission and cognitive dysfunction in schizophrenia because they show that reducing prefrontal inhibitory transmission induces various cognitive, emotional, and dopaminergic abnormalities that resemble aspects of the disorder. These converging clinical and preclinical findings provide strong support for the idea that perturbations in GABA signaling drive certain forms of cognitive dysfunction in schizophrenia. Future studies using this approach will yield information to refine further a putative "GABA hypothesis" of schizophrenia.
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Affiliation(s)
- Maric T Tse
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Patrick T Piantadosi
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Stan B Floresco
- Department of Psychology and Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
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Patel AB, de Graaf RA, Rothman DL, Behar KL. Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo. J Neurosci Res 2015; 93:1101-8. [PMID: 25663257 DOI: 10.1002/jnr.23548] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 11/14/2014] [Accepted: 12/02/2014] [Indexed: 12/24/2022]
Abstract
γ-Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT-1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA-glutamine (Gln) cycle. Halothane-anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6-(13)C2]glucose (in vivo) or [2-(13)C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and (13)C enrichments were measured with (1)H-[(13)C]-nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts from in situ frozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the (13)C turnover data measured in vivo during [1,6-(13)C2]glucose infusion. Tiagabine-treated rats were indistinguishable (P > 0.05) from controls in tissue amino acid levels and in (13)C enrichments from [2-(13)C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (↓18%, CMR(glc(ox)Glu): control, 0.27 ± 0.05 vs. tiagabine, 0.22 ± 0.04 µmol/g/min; ↓11%, V(cyc(Glu-Gln)): control 0.23 ± 0.05 vs. tiagabine 0.21 ± 0.04 µmol/g/min and GABAergic neurons (↓18-25%, CMR(glc(ox)GABA): control 0.09 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min; V(cyc(GABA-Gln)): control 0.08 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P > 0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects.
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Affiliation(s)
- Anant B Patel
- Department of Diagnostic Radiology and the Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut
- CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
| | - Robin A de Graaf
- Department of Diagnostic Radiology and the Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut
| | - Douglas L Rothman
- Department of Diagnostic Radiology and the Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut
| | - Kevin L Behar
- Department of Psychiatry and the Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut
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Finnema SJ, Scheinin M, Shahid M, Lehto J, Borroni E, Bang-Andersen B, Sallinen J, Wong E, Farde L, Halldin C, Grimwood S. Application of cross-species PET imaging to assess neurotransmitter release in brain. Psychopharmacology (Berl) 2015; 232:4129-57. [PMID: 25921033 PMCID: PMC4600473 DOI: 10.1007/s00213-015-3938-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 04/09/2015] [Indexed: 01/03/2023]
Abstract
RATIONALE This review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain. OBJECTIVES Although PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) "Novel Methods leading to New Medications in Depression and Schizophrenia" (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, "Cross-species and neurochemical imaging (PET) methods for drug discovery", commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain. RESULTS Sharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions. CONCLUSIONS PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.
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Affiliation(s)
- Sjoerd J. Finnema
- />Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
| | - Mika Scheinin
- />Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland , />Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland
| | - Mohammed Shahid
- />Research and Development, Orion Corporation, Orion Pharma, Turku, Finland
| | - Jussi Lehto
- />Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
| | - Edilio Borroni
- />Neuroscience Department, Hoffman-La Roche, Basel, Switzerland
| | | | - Jukka Sallinen
- />Research and Development, Orion Corporation, Orion Pharma, Turku, Finland
| | - Erik Wong
- />Neuroscience Innovative Medicine Unit, AstraZeneca, Wilmington, DE USA
| | - Lars Farde
- />Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden , />Translational Science Center at Karolinska Institutet, AstraZeneca, Stockholm, Sweden
| | - Christer Halldin
- />Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden
| | - Sarah Grimwood
- Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, USA. .,, 610 Main Street, Cambridge, MA, 02139, USA.
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Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers. Neuropharmacology 2015; 88:155-63. [DOI: 10.1016/j.neuropharm.2014.08.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Revised: 07/13/2014] [Accepted: 08/21/2014] [Indexed: 11/23/2022]
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Quelch D, De Santis V, Strege A, Myers J, Wells L, Nutt D, Lingford-Hughes A, Parker C, Tyacke R. Influence of agonist induced internalization on [3H]Ro15-4513 binding-an application to imaging fluctuations in endogenous GABA with positron emission tomography. Synapse 2014; 69:60-5. [DOI: 10.1002/syn.21780] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 08/12/2014] [Accepted: 08/27/2014] [Indexed: 02/05/2023]
Affiliation(s)
- Darren Quelch
- Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College; London UK
| | | | | | - James Myers
- Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College; London UK
| | - Lisa Wells
- Imanova Centro for Imaging Sciences; London UK
| | - David Nutt
- Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College; London UK
| | - Anne Lingford-Hughes
- Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College; London UK
| | | | - Robin Tyacke
- Centre for Neuropsychopharmacology; Division of Brain Sciences; Imperial College; London UK
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