Weak effects of local and systemic administration of the GABA uptake inhibitor, SK&amp;F 89976, on extracellular GABA in the rat striatum

Waldmeier, P. C.; Stöcklin, K.; Feldtrauer, Jean-Jacques

doi:10.1007/bf00168946

Cited by 15 publications

(11 citation statements)

References 8 publications

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“…However, previous results from the normal rodent striatum suggested an increase of [GABA] ec after pharmacological block of GAT-1 (Waldmeier et al, 1992; Kirmse et al, 2008). This result is now confirmed and extended by showing that the NO-711-induced increase of GABA uptake was even larger in HD.…”

Section: Discussionmentioning

confidence: 86%

Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3

Wójtowicz

Dvorzhak

Semtner

et al. 2013

Front. Neural Circuits

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The extracellular concentration of the two main neurotransmitters glutamate and GABA is low but not negligible which enables a number of tonic actions. The effects of ambient GABA vary in a region-, cell-type, and age-dependent manner and can serve as indicators of disease-related alterations. Here we explored the tonic inhibitory actions of GABA in Huntington's disease (HD). HD is a devastating neurodegenerative disorder caused by a mutation in the huntingtin gene. Whole cell patch clamp recordings from striatal output neurons (SONs) in slices from adult wild type mice and two mouse models of HD (Z_Q175_KI homozygotes or R6/2 heterozygotes) revealed an HD-related reduction of the GABA(A) receptor-mediated tonic chloride current (ITonic(GABA)) along with signs of reduced GABA(B) receptor-mediated presynaptic depression of synaptic GABA release. About half of ITonic(GABA) depended on tetrodotoxin-sensitive synaptic GABA release, but the remaining current was still lower in HD. Both in WT and HD, ITonic(GABA) was more prominent during the first 4 h after preparing the slices, when astrocytes but not neurons exhibited a transient depolarization. All further tests were performed within 1–4 h in vitro. Experiments with SNAP5114, a blocker of the astrocytic GABA transporter GAT-3, suggest that in WT but not HD GAT-3 operated in the releasing mode. Application of a transportable substrate for glutamate transporters (D-aspartate 0.1–1 mM) restored the non-synaptic GABA release in slices from HD mice. ITonic(GABA) was also rescued by applying the hyperagonist gaboxadol (0.33 μM). The results lead to the hypothesis that lesion-induced astrocyte depolarization facilitates non-synaptic release of GABA through GAT-3. However, the capacity of depolarized astrocytes to provide GABA for tonic inhibition is strongly reduced in HD.

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Section: Discussionmentioning

confidence: 86%

Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3

Wójtowicz

Dvorzhak

Semtner

et al. 2013

Front. Neural Circuits

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“…Another controversy in the literature is the inability to detect effects of GABA B autoreceptor agonists such as baclofen (Richards et al . 1995; Waldmeier et al . 1992; Timmerman et al .…”

Section: Discussionmentioning

confidence: 99%

“…1993; Lambert and Wilson 1994). However, in microdialysis studies, administration of baclofen is reported to have little (Bourdelais and Kalivas 1992) or no effect (Waldmeier et al . 1992; Richards et al .…”

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confidence: 99%

HPLC conditions are critical for the detection of GABA by microdialysis

Rea

Cremers

Westerink

2005

Journal of Neurochemistry

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In microdialysis studies, neither exocytotic release of c-aminobutyric acid (GABA), nor the presence of GABA type B (GABA B ) autoreceptors, have been clearly established. It was investigated whether the chromatographic separation of GABA may have contributed to discrepancies in the literature. After extending the profile of the HPLC chromatogram to a retention time of 60 min, it was observed that various unknown compounds of biological origin co-eluted near the GABA peak. The retention time of GABA appeared to be extremely sensitive to pH; even at a retention time of around 60 min there was only a small pH window (5.26 ± 0.01) where GABA was consistently well separated from co-eluting compounds. GABA determined by the improved assay was sensitive to tetrodotoxin (TTX), calcium depletion and the GABA B autoreceptor agonist baclofen. The present results illustrate that if the proper analytical conditions are applied, extracellular GABA can be sampled and quantified by microdialysis in free-moving animals. However, when the time-curves are considered, there is a striking delay of about 15-30 min before the effects of TTX, calcium depletion or baclofen are observed, as compared to the reported response of neurotransmitters such as dopamine (less than 5 min). It is assumed that the glial cells serve as a buffer between the GABA synapse and the microdialysis probes. It is proposed that microdialysis samples measure synaptic GABA indirectly, through glial cells surrounding the synapses.

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“…The GABA uptake inhibitors tiagabine and NNC-711 were also reported to elevate extracellular GABA levels (Fink-Jensen et al, 1992;Rowley et al, 1995, respectively). The selective uptake inhibitor SKF 89976, although lacking displacement characteristics (Yunger et al, 1984), nonetheless increased GABA levels (Waldmeier et al, 1992a), but again the stimulated extracellular levels were found to be TTXinsensitive (Timmerman and Westerink, 1997). This lack of TTX-sensitivity is difficult to explain.…”

Section: The Use Of (Re)uptake Inhibitorsmentioning

confidence: 99%

Brain microdialysis of GABA and glutamate: What does it signify?

Timmerman

Westerink

1997

Synapse

375

194

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Microdialysis has become a frequently used method to study extracellular levels of GABA and glutamate in the central nervous system. However, the fact that the major part of GABA and glutamate as measured by microdialysis does not fulfill the classical criteria for exocytotic release questions the vesicular origin of the amino acids in dialysates. Glial metabolism or reversal of the (re)uptake sites has been suggested to be responsible for the pool of nonexocytotically released amino-acid transmitters that seem to predominate over the neuronal exocytotic pool. The origin of extracellular GABA and glutamate levels and, as a consequence, the implications of changes in these levels upon manipulations are therefore obscure. This review critically analyzes what microdialysis data signify, i.e., whether amino-acid neurotransmitters sampled by microdialysis represent synaptic release, carrier-mediated release, or glial metabolism. The basal levels of GABA and glutamate are virtually tetrodotoxin- and calcium-independent. Given the fact that evidence for nonexocytotic release mediated by reversal of the uptake sites as a release mechanism relevant for normal neurotransmission is so far limited to conditions of "excessive stimulation," basal levels most likely reflect a nonneuronal pool of amino acids. Extracellular GABA and glutamate concentrations can be enhanced by a wide variety of pharmacological and physiological manipulations. However, it is presently impossible to ascertain that the stimulated GABA and glutamate in dialysates are of neuronal origin. On the other hand, under certain stimulatory conditions, increases in amino-acid transmitters can be obtained in the presence of tetrodotoxin, again suggesting that aspecific factors not directly related to neurotransmission underlie these changes in extracellular levels. It is concluded that synaptic transmission of GABA and glutamate is strictly compartmentalized and as a result, these amino acids can hardly leak out of the synaptic cleft and reach the extracellular space where the dialysis probe samples.

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Weak effects of local and systemic administration of the GABA uptake inhibitor, SK&F 89976, on extracellular GABA in the rat striatum

Cited by 15 publications

References 8 publications

Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3

Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3

HPLC conditions are critical for the detection of GABA by microdialysis

Brain microdialysis of GABA and glutamate: What does it signify?

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