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      Effects of common anesthetic agents on [ 18F]flumazenil binding to the GABA A receptor

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          Abstract

          Background

          The availability of GABA A receptor binding sites in the brain can be assessed by positron emission tomography (PET) using the radioligand, [ 18F]flumazenil. However, the brain uptake and binding of this PET radioligand are influenced by anesthetic drugs, which are typically needed in preclinical imaging studies and clinical imaging studies involving patient populations that do not tolerate relatively longer scan times. The objective of this study was to examine the effects of anesthesia on the binding of [ 18F]flumazenil to GABA A receptors in mice.

          Methods

          Brain and whole blood radioactivity concentrations were measured ex vivo by scintillation counting or in vivo by PET in four groups of mice following administration of [ 18F]flumazenil: awake mice and mice anesthetized with isoflurane, dexmedetomidine, or ketamine/dexmedetomidine. Dynamic PET recordings were obtained for 60 min in mice anesthetized by either isoflurane or ketamine/dexmedetomidine. Static PET recordings were obtained at 25 or 55 min after [ 18F]flumazenil injection in awake or dexmedetomidine-treated mice acutely anesthetized with isoflurane. The apparent distribution volume (V T*) was calculated for the hippocampus and frontal cortex from either the full dynamic PET scans using an image-derived input function or from a series of ex vivo experiments using whole blood as the input function.

          Results

          PET images showed persistence of high [ 18F]flumazenil uptake (up to 20 % ID/g) in the brains of mice scanned under isoflurane or ketamine/dexmedetomidine anesthesia, whereas uptake was almost indiscernible in late samples or static scans from awake or dexmedetomidine-treated animals. The steady-state V T* was twofold higher in hippocampus of isoflurane-treated mice and dexmedetomidine-treated mice than in awake mice.

          Conclusions

          Anesthesia has pronounced effects on the binding and blood-brain distribution of [ 18F]flumazenil. Consequently, considerable caution must be exercised in the interpretation of preclinical and clinical PET studies of GABA A receptors involving the use of anesthesia.

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          Most cited references41

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          GABA A receptors: subtypes provide diversity of function and pharmacology.

          This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist. GABA(A) receptors are chloride channels that mediate inhibitory neurotransmission. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. They are assembled from a family of 19 homologous subunit gene products and form numerous receptor subtypes with properties that depend upon subunit composition, mostly hetero-oligomeric. These vary in their regulation and developmental expression, and importantly, in brain regional, cellular, and subcellular localization, and thus their role in brain circuits and behaviors. We propose several criteria for including a receptor hetero-oligomeric subtype candidate on a list of native subtypes, and a working GABA(A) receptor list. These criteria can be applied to all the members of the LGIC superfamily. The list is divided into three categories of native receptor subtypes: "Identified", "Existence with High Probability", and "Tentative", and currently includes 26 members, but will undoubtedly grow, with future information. This list was first presented by Olsen & Sieghart (in press).
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            Structure, function, and modulation of GABA(A) receptors.

            The GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABA(A) receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABA(A) receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects.
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              GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.

              GABA(A) receptors are ligand-operated chloride channels assembled from five subunits in a heteropentameric manner. Using immunocytochemistry, we investigated the distribution of GABA(A) receptor subunits deriving from 13 different genes (alpha1-alpha6, beta1-beta3, gamma1-gamma3 and delta) in the adult rat brain. Subunit alpha1-, beta1-, beta2-, beta3- and gamma2-immunoreactivities were found throughout the brain, although differences in their distribution were observed. Subunit alpha2-, alpha3-, alpha4-, alpha5-, alpha6-, gamma1- and delta-immunoreactivities were more confined to certain brain areas. Thus, alpha2-subunit-immunoreactivity was preferentially located in forebrain areas and the cerebellum. Subunit alpha6-immunoreactivity was only present in granule cells of the cerebellum and the cochlear nucleus, and subunit gamma1-immunoreactivity was preferentially located in the central and medial amygdaloid nuclei, in pallidal areas, the substantia nigra pars reticulata and the inferior olive. The alpha5-subunit-immunoreactivity was strongest in Ammon's horn, the olfactory bulb and hypothalamus. In contrast, alpha4-subunit-immunoreactivity was detected in the thalamus, dentate gyrus, olfactory tubercle and basal ganglia. Subunit alpha3-immunoreactivity was observed in the glomerular and external plexiform layers of the olfactory bulb, in the inner layers of the cerebral cortex, the reticular thalamic nucleus, the zonal and superficial layers of the superior colliculus, the amygdala and cranial nerve nuclei. Only faint subunit gamma3-immunoreactivity was detected in most areas; it was darkest in midbrain and pontine nuclei. Subunit delta-immunoreactivity was frequently co-distributed with alpha4 subunit-immunoreactivity, e.g. in the thalamus, striatum, outer layers of the cortex and dentate molecular layer. Striking examples of complementary distribution of certain subunit-immunoreactivities were observed. Thus, subunit alpha2-, alpha4-, beta1-, beta3- and delta-immunoreactivities were considerably more concentrated in the neostriatum than in the pallidum and entopeduncular nucleus. In contrast, labeling for the alpha1-, beta2-, gamma1- and gamma2-subunits prevailed in the pallidum compared to the striatum. With the exception of the reticular thalamic nucleus, which was prominently stained for subunits alpha3, beta1, beta3 and gamma2, most thalamic nuclei were rich in alpha1-, alpha4-, beta2- and delta-immunoreactivities. Whereas the dorsal lateral geniculate nucleus was strongly immunoreactive for subunits alpha4, beta2 and delta, the ventral lateral geniculate nucleus was predominantly labeled for subunits alpha2, alpha3, beta1, beta3 and gamma2; subunit alpha1- and alpha5-immunoreactivities were about equally distributed in both areas. In most hypothalamic areas, immunoreactivities for subunits alpha1, alpha2, beta1, beta2 and beta3 were observed. In the supraoptic nucleus, staining of conspicuous dendritic networks with subunit alpha1, alpha2, beta2, and gamma2 antibodies was contrasted by perykarya labeled for alpha5-, beta1- and delta-immunoreactivities. Among all brain regions, the median emminence was most heavily labeled for subunit beta2-immunoreactivity. In most pontine and cranial nerve nuclei and in the medulla, only subunit alpha1-, beta2- and gamma2-immunoreactivities were strong, whereas the inferior olive was significantly labeled only for subunits beta1, gamma1 and gamma2. In this study, a highly heterogeneous distribution of 13 different GABA(A) receptor subunit-immunoreactivities was observed. This distribution and the apparently typical patterns of co-distribution of these GABA(A) receptor subunits support the assumption of multiple, differently assembled GABA(A) receptor subtypes and their heterogeneous distribution within the adult rat brain.
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                Author and article information

                Contributors
                +1 (45) 356-711 , mikael.palner@nru.dk , mikael.palner@gmail.com
                cbeinat@stanford.edu
                samuelb2@stanford.edu
                zanderi@nyspi.columbia.edu
                parkjh@stanford.edu
                binshen@stanford.edu
                trine@stanford.edu
                jjh@bioimaging.co.kr
                leebc@snu.ac.kr
                kse@snu.ac.kr
                lkfung@stanford.edu
                +1 (650) 725-4182 , chinf@stanford.edu
                Journal
                EJNMMI Res
                EJNMMI Res
                EJNMMI Research
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2191-219X
                8 November 2016
                8 November 2016
                2016
                : 6
                : 80
                Affiliations
                [1 ]Departments of Radiology, Stanford University School of Medicine, Stanford, CA USA
                [2 ]Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA USA
                [3 ]Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark
                [4 ]Department of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY USA
                [5 ]Department of Psychiatry, Columbia University, New York, NY USA
                [6 ]The Intervention Centre, Oslo University Hospital, Oslo, Norway
                [7 ]The Norwegian Medical Cyclotron Centre, Oslo, Norway
                [8 ]Bio Imaging Korea Co., Ltd, Seoul, Republic of Korea
                [9 ]Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
                [10 ]Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology, Suwon, Republic of Korea
                [11 ]Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
                [12 ]Department of Radiology, Cyclotron Radiochemistry, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 1201 Welch Road, Rm PS049, Stanford, CA 94305-5484 USA
                Article
                235
                10.1186/s13550-016-0235-2
                5101239
                27826950
                ba3a0196-fe3f-4e3c-b7d1-680836b46559
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 9 August 2016
                : 29 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: ICMIC P50 CA114747
                Funded by: FundRef http://dx.doi.org/10.13039/100000071, National Institute of Child Health and Human Development;
                Award ID: R01 HD084214
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1S10 OD018130
                Award Recipient :
                Categories
                Original Research
                Custom metadata
                © The Author(s) 2016

                Radiology & Imaging
                flumazenil,gabaa receptor,pet,anesthesia,ketamine,isoflurane,dexmedetomidine
                Radiology & Imaging
                flumazenil, gabaa receptor, pet, anesthesia, ketamine, isoflurane, dexmedetomidine

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