GABA induces down-regulation of the benzodiazepine-GABA receptor complex in the rat cultured neurons

Maloteaux, Jean‐Marie; Octave, Jean‐Noël; Gossuin, A.; Laterre, C.; Trouet, André

doi:10.1016/0014-2999(87)90517-6

Cited by 71 publications

(27 citation statements)

References 31 publications

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“…The process, at least for the a I-and a6-subunits, appears to be independent of alterations in the steady-state mRNA levels, and thus is likely to involve posttranscriptional and/or post-translational mechanisms. Agonist-mediated down-regulation of GABAA receptors has been inferred from the reduction in radioligand binding sites associated with the GABAA/benzodiazepine receptor complex after chronic exposure to GABA (Maloteaux et al, 1987;Hablitz et al, 1989;Roca et al, 1990;Mehta & Ticku, 1992). Under similar conditions, the function of the GABAA receptor is decreased (Hablitz et al, 1989) and uncoupling between the GABA and benzodiazepine binding sites has been described (Roca et al, 1990;Mehta & Ticku, 1992).…”

Section: Discussionmentioning

confidence: 99%

The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

Platt

Zwartjes

Bristow

1996

British J Pharmacology

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1 After 8 days in vitro, rat cerebellar granule cells were exposed to 1 mM y-aminobutyric acid (GABA) for periods of 1, 2, 4, 6, 8 and 10 days. The effect of the GABA exposure on GABAA receptor ax, a6 and #2,3 subunit protein expression and al and a6 subunit steady-state mRNA levels, was examined using Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. 2 GABA exposure for 2 days decreased al (35+10%, mean+s.e.mean), ,B2,3 (21+9%) and a6 (28 +10%) subunit protein expression compared to control levels. The GABA-mediated reduction in al subunit expression after 2 days treatment was abolished in the presence of the GABAA receptor antagonist, Ru 5135 (10 uM). 3 GABA exposure for 8 days increased al (26+10%, mean+s.e.mean) and ,B2,3 (56+23%) subunit protein expression over control levels, whereas a6 subunit protein expression remained below control levels (by 38+10%). However, after 10 days GABA exposure, a6 subunit protein expression was also increased over control levels by 65+29% (mean + s.e.mean). 4 GABA exposure did not change the al or a6 subunit steady-state mRNA levels over an 8 day period, nor did it alter the expression of cyclophilin mRNA over 1-8 days. 5 These results suggest that chronic GABA exposure of rat cerebellar granule cells has a bi-phasic effect on GABAA receptor subunit expression that is independent of changes to mRNA levels. Therefore, the regulation of the GABAA receptor expression by chronic agonist treatment appears to involve posttranscriptional and/or post-translational processes.

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Section: Discussionmentioning

confidence: 99%

The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

Platt

Zwartjes

Bristow

1996

British J Pharmacology

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“…Regarding the first possibility, the reported threefold increase of CSF GABA levels (from 4-5 to 12-14 nmoV ml) with VGB (4-8) indicates that extraneuronal GABA levels do substantially increase and with the same order of magnitude as total tissue levels measured with MRS (from 1.04 to 2.37 pmol/g) (3,14). The almost 1,000-fold discrepancy in magnitude between the CSF and totaltissue GABA levels is compatible with the hypothesis that the majority of the increased GABA is being captured by neuronal and astrocytic GABA transporters before it reaches the postsynaptic BZR.…”

Section: Discussionmentioning

confidence: 99%

“…GABA MRS was performed as previously described (3,22) with a 2.1-T I-m bore magnet (Oxford Magnet Technologies, Oxford, U.K.) equipped with an extensively modified Biospec I spectrometer (Bruker Instruments, Billerica, MA, U.S.A.). A rectangular volume of interest (VOI) of 3 x 2 x 2 cc over the OC was used for the spectroscopic measurements.…”

Section: Gaba Mrsmentioning

confidence: 99%

“…These results are similar to the recent ["C]flumazenil PET study in healthy subjects that failed to show any BZR downregulation after much shorter treatment with VGB (14). These results suggest that either the intrasynaptic increase of GABA is insufficient to induce BZR downregulation or that BZR do not respond in vivo with long-term downregulation to increased intrasynaptic GABA levels.Regarding the first possibility, the reported threefold increase of CSF GABA levels (from 4-5 to 12-14 nmoV ml) with VGB (4-8) indicates that extraneuronal GABA levels do substantially increase and with the same order of magnitude as total tissue levels measured with MRS (from 1.04 to 2.37 pmol/g) (3,14). The almost 1,000-fold discrepancy in magnitude between the CSF and totaltissue GABA levels is compatible with the hypothesis that the majority of the increased GABA is being captured by neuronal and astrocytic GABA transporters before it reaches the postsynaptic BZR.…”

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confidence: 99%

“…VGB may in addition compete with GABA for the neuronal GABA transporter (2). A previous study using 'H nuclear magnetic resonance spectroscopy (MRS) showed a twofold elevation of occipital cor- (3). The vast majority of tissue GABA measured by MRS is intracellular.…”

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Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

et al. 1999

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Summary:Purpose: To evaluate effects of vigabatrin (VGB) by using [1231)iomazenil single-photon emission computed tomography (SPECT) to estimate central y-aminobutyric acid (GABA,)/benzodiazepine receptors (BZRs), and magnetic resonance spectroscopy (MRS) to assess tissue GABA levels.Methods: Six patients with partial seizures had both SPECT and MRS before and 25-84 days after starting VGB (3 g P.o., q.d.). SPECT was acquired by using the constant-infusion method and, after nonuniform attenuation correction, coregistered with T,-weighted MR Imaging (MRI) A volume of interest (VOI) of 3 x 2 x 2 cc over the occipital cortex, used for MRS acquisition, was positioned on both MRI and coregistered SPECT. Occipital activity was divided by either total plasma activity or plasma [1231]iomazenil concentration to estimate BZR distribution volume (V,-p and Vk, respectively). Wilcoxon's test was used for VOI differences in GABA levels, BZR V,-p or V;. SPM96 (either no global normalization or proportional scaling) was used to compare BZR V,-p changes in the patients with and without VGB with test-retest data in eight healthy age-matched controls.Results: Occipital GABA levels were increased threefold (without VGB, 1.1 -t 0.1 pmol/g; with VGB, 2.9 & 0.5 pmol/g; p = 0.027). BZR distribution volumes showed no change, when estimated by either V,-p (without VGB, 6.00 2 0.91 mllg; with VGB, 5.86 k 0.44 ml/g; p = 0.92) or V; (without VGB, 41.1 2 11.2 ml/g; with VGB, 41.2 _t 9.9 ml/g; p = 0.75). No significant changes were detected by SPM96.Conclusions: A clinically effective dose of VGB caused a threefold increase in tissue GABA levels but was not associated with a substantial BZR downregulation. Key Words: Vigabatrin-Benzodiazepine receptor-SPECT-GAB A-MRS .y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in human cerebral cortex. Animal models show that GABA plays a pivotal role in suppressing the origin and spread of seizure activity. The antiepileptic drug (AED) vigabatrin (VGB; y-vinyl GABA, or 4-amino-hex-5-enoic acid) irreversibly inhibits GABA transaminase, preferentially in neurons but also in astrocytes, markedly increasing GABA concentrations in vitro and in vivo (1). VGB may in addition compete with GABA for the neuronal GABA transporter (2). A previous study using 'H nuclear magnetic resonance spectroscopy (MRS) showed a twofold elevation of occipital cor- (3). The vast majority of tissue GABA measured by MRS is intracellular. Nevertheless, the increased tissue GABA levels induced by VGB probably also reflect the extracellular pool of GABA, which interacts with and may modulate GABA*ibenzodiazepine receptors (BZR) levels. That is, lumbar cerebrospinal fluid (CSF) GABA concentrations also are increased threefold with daily VGB therapy, and the increased CSF GABA concentrations correlate with improved seizure control (4)(5)(6)(7)(8). Therefore the increase in GABA levels appears to be critical to the efficacy of VGB .Alterations in BZR may modulate the effect of increased GABA levels. For example, incr...

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Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

Malizia

Cunningham²,

Bell³

et al. 1998

Arch Gen Psychiatry

337

155

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GABA induces down-regulation of the benzodiazepine-GABA receptor complex in the rat cultured neurons

Cited by 71 publications

References 31 publications

The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS

Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

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GABA induces down-regulation of the benzodiazepine-GABA receptor complex in the rat cultured neurons

Cited by 71 publications

References 31 publications

The effect of GABA stimulation on GABAA receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

The effect of GABA stimulation on GABAA receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

Effects of Vigabatrin on the GABAergic System as Determined by [123I]Iomazenil SPECT and GABA MRS

Decreased Brain GABAA-Benzodiazepine Receptor Binding in Panic Disorder

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The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

The effect of GABA stimulation on GABA_A receptor subunit protein and mRNA expression in rat cultured cerebellar granule cells

Effects of Vigabatrin on the GABAergic System as Determined by [¹²³I]Iomazenil SPECT and GABA MRS