Decreased expression of γ-aminobutyric acid type A/benzodiazepine receptor beta subunit mRNAs in brain of flurazepam-tolerant rats

Zhao, Tai-Jun; Chiu, Ted H.; Rosenberg, Howard C.

doi:10.1007/bf02736732

Cited by 39 publications

(48 citation statements)

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“…13 Although the synaptic mechanisms mediating benzodiazepine tolerance have not been determined, evidence has accumulated that a change in subunit-specific expression of neuronal GABA A receptor subtypes may modify inhibitory function during long-term benzodiazepine treatment. 21,22,27,29,30,44,49,65,66,80,81 Consistent with this hypothesis, time-dependent changes in the mRNA expression of specific GABA A receptor subunits (a1, b2 and b3) were localized to distinct hippocampal and cerebral cortical cell groups, 65,66 following one-week oral flurazepam administration. None the less, no direct link has been provided between changes in GABA A receptor subunit mRNA expression, changes in subunit protein expression and changes in GABA A receptor function.…”

mentioning

confidence: 56%

“…37 It will be important to determine the temporal pattern of changes in subunit protein expression following chronic benzodiazepine administration in comparison to the time-course of the change in the expression of GABA A receptor subunit mRNAs. 17,22,27,29,44,65,66,80,81 Such information may help to clarify the relationship between changes in protein expression (e.g., of a1, b2 and b3 subunits) and changes in the GABAergic function of some (CA1 pyramidal cells), but not other (CA3 pyramidal cells and dentate granule cells), hippocampal principal cell types in benzodiazepine-tolerant rats. 28,47,48,75,76,78 …”

Section: Discussionmentioning

confidence: 99%

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Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

et al. 1999

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Abstract-Prolonged flurazepam exposure regulates the expression of selected (a1, b2, b3) GABA A receptor subunit messenger RNAs in specific regions of the hippocampus and cortex with a time-course consistent with benzodiazepine tolerance both in vivo and in vitro. In this report, the immunostaining density of six specific GABA A receptor subunit (a1, a2, b1-3 and g2) antibodies was measured in the hippocampus and cortex, among other brain areas, in slide-mounted brain sections from flurazepam-treated and control rats using quantitative computer-assisted image analysis techniques. In parallel with the localized reduction in a1 and b3 subunit messenger RNA expression detected in a previous study, relative a1 and b3 subunit antibody immunostaining density was significantly decreased in flurazepam-treated rat hippocampal CA1, CA3 and dentate dendritic regions, and in specific cortical layers. Quantitative western blot analysis showed that b3 subunit protein levels in crude homogenates of the hippocampal dentate region from flurazepam-treated rats, an area which showed fairly uniform decreases in b3 subunit immunostaining (16-21%), were reduced to a similar degree (18%). The latter findings provide independent support that relative immunostaining density may provide an accurate estimate of protein levels. Consistent with the absence of the regulation of their respective messenger RNAs immediately after ending flurazepam administration, no changes in the density of a2, b1 or b2 subunit antibody immunostaining were found in any brain region. g2 subunit antibody staining was changed only in the dentate molecular layer.The selective changes in GABA A receptor subunit antibody immunostaining density in the hippocampus suggested that a change in the composition of GABA A receptors involving specific subunits (a1 and b3) may be one mechanism underlying benzodiazepine anticonvulsant tolerance. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.Key words: tolerance, flurazepam, quantitative immunohistochemistry, dentate gyrus, limbic system, CA1 pyramidal cells.Although effective anxiolytics and hypnotics, the clinical use of benzodiazepines as anticonvulsants is limited by tolerance development during prolonged administration. A large body of evidence has indicated that benzodiazepine tolerance is related to a reduction in GABA A receptor-mediated fast inhibitory synaptic transmission (for reviews see Refs 2 and 27). The native GABA A receptor is a pentamer composed of combinations of homologous proteins derived from five subunit families with multiple variants (a1-6, b1-4, g1-3, d1 and e1). 8,11,34 The GABA A receptor macromolecule contains binding domains for GABA and several allosteric modulators, including a well-characterized benzodiazepine binding site. 59Benzodiazepines potentiate GABA A receptor-mediated inhibitory function by increasing the opening probability of the integral Cl Ϫ channel, 52,62 and may increase Cl Ϫ channel conductance. 13Although the synaptic mechanisms mediating benzodiazepine tolerance have not been...

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confidence: 56%

Section: Discussionmentioning

confidence: 99%

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

et al. 1999

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“…Nevertheless, the overall tendency suggests an enhanced expression, although seizure activity may, transiently, depress mRNA expression. In contrast, several studies on the effects of long-lasting application of GABAAR agonists to cultured neurons, or the continuous treatment of animals with benzodiazepines, have quite consistently reported a decreased expression of the GABAAR subunits al, a2, a3, a5 and 3'2, which has been related to reduced GABAAR mediated functions [16,42,48,65,80]. The administration of the inverse benzodiazepine agonist, FG 7142, for several days increased al and 3'2, while treatment with diazepam resulted in decreased levels [56].…”

Section: Gaba Ar Subunit Mrna Expression In Other Models Of Synaptic mentioning

confidence: 98%

“…By altering the expression pattern of GABAAR subunit encoding genes, neurons may have the ability to fine tune their GABAergic signal transduction pathway in response to changing conditions. Changes in subunit expression profile during development [30] and in response to transient cerebral ischemia [33], chronic GABAA/benzodiazepine receptor agonists/antagonists [15,25,42,56,63,80] or ethanol treatment [41,44,49] may underly functional changes of GABAARS. Modified GABAAR subunit mRNA levels were also described in rats that were subjected to repeated electrical stimulations with short interstimulus intervals resuiting in recurrent epileptiform seizures (rapid kindling procedure) [27].…”

Section: Introductionmentioning

confidence: 99%

Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

Kamphuis

Rijk

Silva

1995

Molecular Brain Research

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Expression of GABA-A receptor subunit in mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study. Kamphuis, W.; de Rijk, T.C.; Lopes da Silva, F.H. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Accepted 24 January 1995 AbstractTo investigate the molecular changes underlying kindling epileptogenesis in the rat hippocampus, the expression levels of the genes encoding for 13 different y-aminobutyric acid type-A receptor (GABAAR) subunits were measured in hippocampal principal neurons using in situ hybridization techniques and semi-quantitative analysis of the autoradiograms. Schaffer collateral-commissural pathway kindled rats were investigated at three different stages of kindling acquisition, at 24 h after the last seizure and at long-term (28 days) after termination of kindling stimulations. Changes were distinct for the different subunits in the three analyzed regions (CA1, CA3, fascia dentata) and also different for the various kindling stages. In all hippocampal areas at the early phases of kindling epileptogenesis, before the appearance of generalized seizures, an increase was found of those transcripts that constituted the majority of the expressed variants in control animals (al, a2, a4, /31, /32, /33, y2/y2L mRNA). In these stages, the increased levels of different variants in the granular neurons of the fascia dentata were more pronounced when compared to the pattern of changes in pyramidal cells of CA1 and CA3. In fully kindled animals, the expression levels of several subunits returned to control levels, whereas/33 and y2/y2L mRNA expression was still significantly enhanced in all areas. At long-term, few changes were encountered. The long-splice variant of 3,2 was decreased within pyramidal and granular neurons while the total level of y2 mRNA was not different from controls. The increased GABAAR subunit expression in the fascia dentata may underly the reported increased GABAAR ligand binding and the increased GABA mediated inhibition. However, the decreased GABAAR binding and the attenuation of GABAergic inhibition in CA1, could not be explained by a decrement of receptor subunit expression.

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“…The Y2 subunit is a good candidate as there is evidence that this subunit is required for a robust enhancement of GABA function. Indeed, there is some evidence of changes in the mRNA for Y2 in the hippocampus and cortex after chronic high dose flurazepam treatment (Zhao et al, 1994). However, our preliminary findings, using in situ hybridization, do not support changes in Y2 or c, and X4 subunit expression as a mechanism for the altered BZ/GABA coupling observed after chronic diazepam treatment in the present study (Corda & Biggio, 1986 (Friedman et al, 1986), whereas the implanted animals will receive continuous exposure to a lower level of the drug.…”

Section: Gabaa Receptormentioning

confidence: 99%

Changes in benzodiazepine‐GABA receptor coupling in an accumbens‐habenula circuit after chronic diazepam treatment

Brett

Pratt

1995

British J Pharmacology

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4 In general, the patterns of binding produced by the two different treatment routes were very similar. However, SR 95531 binding was lower in certain hippocampal fields in the i.p. treated animals compared to the rats implanted with silastic capsules. 5 It is concluded that repeated administration of diazepam evokes changes in benzodiazepine and GABA receptor coupling, and to a lesser extent changes in low affinity GABA binding, in certain interrelated brain structures of which an accumbens-habenula circuit is a central feature. These changes occur soon after the initiation of diazepam treatment, suggesting that they are unlikely to account for tolerance to the anxiolytic effects of diazepam but may trigger and/or accompany other critical neurochemical events.

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Decreased expression of γ-aminobutyric acid type A/benzodiazepine receptor beta subunit mRNAs in brain of flurazepam-tolerant rats

Cited by 39 publications

References 43 publications

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Benzodiazepine-mediated regulation of α1, α2, β1–3 and γ2 GABAA receptor subunit proteins in the rat brain hippocampus and cortex

Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

Changes in benzodiazepine‐GABA receptor coupling in an accumbens‐habenula circuit after chronic diazepam treatment

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