Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes

Mantz, Jean; Lecharny, Jean-Baptiste; Laudenbach, Vincent; Henzel, D.; Peytavin, Gilles; Desmonts, Jean-Marie

doi:10.1097/00000542-199502000-00020

Cited by 61 publications

(26 citation statements)

References 37 publications

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“…In our experiments, 1 mM of nipecotic acid, which has been shown to inhibit GABA re-uptake in rat striatal synaptosomes by more than 95% (Mantz et al, 1995), increased the amount of GABA out¯ow by 6.55 times. Assuming that nipecotic acid did not signi®cantly augment the GABA release, it can be estimated that when nipecotic acid is absent, the amount of GABA di used from the slices into the ACSF was less than 15% of the actual amount released from the presynaptic membrane.…”

Section: Discussionmentioning

confidence: 45%

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Liachenko

Tang

Somogyi

et al. 1999

British J Pharmacology

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1 The synaptic concentrations of glutamate and g-aminobutyric acid (GABA) are modulated by their release and re-uptake. The e ects of general anaesthetics on these two processes remain unclear. This study evaluates the e ects of iso¯urane, a clinically important anaesthetic, on glutamate and GABA release and re-uptake in superfused mouse cerebrocortical slices. 2 Experiments consisted of two 1.5-min exposures to 40 mM KCl in 30 min intervals. During the second exposure, di erent concentrations of iso¯urane with and without 0.3 mM L-transpyrrolidine-2,4-dicarboxylic acid (PDC, a competitive inhibitor of glutamate uptake transporter) or 1 mM nipecotic acid (a competitive inhibitor of GABA uptake transporter) were introduced. The ratios of the second to ®rst KCl-evoked increases in glutamate and GABA were used to determine the iso¯urane concentration-response curves.3 The results can be described as a sum of two independent processes, corresponding to the inhibitions of release and re-uptake, respectively. The EC 50 values for the inhibitions of release and re-uptake were 295+16 and 805+43 mM for glutamate, and 229+13 and 520+25 mM for GABA, respectively. Addition of PDC did not signi®cantly a ect glutamate release but shifted the re-uptake curve to the left (EC 50 =315+20 mM). Nipecotic acid completely blocked GABA uptake, rendering iso¯urane inhibition of GABA re-uptake undetectable. 4 Our data suggest that iso¯urane inhibits both the release and re-uptake of neurotransmitters and that the inhibitions occur at di erent EC 50 's. For GABA, both EC 50 's are within the clinical concentration range. The net anaesthetic e ect on extracellular concentrations of neurotransmitters, particularly GABA, depends on the competition between inhibition of release and that of re-uptake.

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Section: Discussionmentioning

confidence: 45%

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Liachenko

Tang

Somogyi

et al. 1999

British J Pharmacology

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“…Ketamine is a competitive inhibitor of the transport of [ 3 H]NA, [ 3 H]DA and [ 3 H]5-HT in rat brain synaptosomes (Azzaro and Smith 1977;Martin et al 1988). On the other hand, ketamine is reported to inhibit γ-aminobutyric acid (GABA) transport in a non-competitive manner (Mantz et al 1995). Furthermore, the site of action of ketamine on the transporters is unknown.…”

Section: Introductionmentioning

confidence: 99%

Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site

Hara

Yanagihara

Minami

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

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Effects of the intravenous anaesthetic ketamine on the desipramine-sensitive noradrenaline transporter (NAT) were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NAT (bNAT). Incubation (1-3 h) of adrenal medullary cells with ketamine (10-300 microM) caused an increase in appearance of catecholamines in culture medium. Ketamine (10-1000 microM) inhibited desipramine-sensitive uptake of [3H]noradrenaline (NA) (IC50=97 microM). Saturation analysis showed that ketamine reduced Vmax of [3H]NA uptake without changing Km, indicating a non-competitive inhibition. Other inhibitors of NAT, namely cocaine and desipramine, showed a competitive inhibition of [3H]NA uptake while a derivative of ketamine, phencyclidine, showed a mixed type of inhibition. Ketamine (10-1000 microM) also inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [3H]desipramine binding revealed that ketamine increased Kd without altering Bmax, indicating a competitive inhibition. In transfected Xenopus oocytes expressing the bNAT, ketamine attenuated [3H]NA uptake with a kinetic characteristic similar to that of cultured adrenal medullary cells. These findings are compatible with the idea that ketamine non-competitively inhibits the transport of NA by interacting with a site which partly overlaps the desipramine binding site on the NAT.

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“…Volatile general anesthetics have been reported previously to have small effects on basal release of glutamate from isolated nerve terminals (synaptosomes) (Hirose et al, 1992;Miao et al, 1995;Schlame and Hemmings, 1995;Westphalen and Hemmings, 2003a) and tissue slices (Bickler et al, 1995;Toner et al, 2001) and of GABA from synaptosomes (Hirose et al, 1992;Mantz et al, 1995;Westphalen and Hemmings, 2003a), which were considered as insignificant. However, even small changes in basal transmitter release may have significant effects on CNS function (Cavelier et al, 2005).…”

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confidence: 99%

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: Basal Release

Westphalen¹,

Hemmings²

2005

J Pharmacol Exp Ther

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The effects of three volatile anesthetics (isoflurane, enflurane, and halothane) on basal release of glutamate and GABA from isolated rat cerebrocortical nerve terminals (synaptosomes) were compared using a dual isotope superfusion method. Concentration-dependent effects on basal release differed between anesthetics and transmitters. Over a range of clinical concentrations (0.5-2ϫ minimum alveolar concentration), basal glutamate release was inhibited by all three anesthetics, whereas basal GABA release was enhanced (isoflurane) or unaffected (enflurane and halothane). These effects may represent a balance of stimulatory and inhibitory mechanisms between transmitters and anesthetics. There were no significant differences between anesthetic effects on basal release in the absence or presence of external Ca 2ϩ , whereas intracellular Ca 2ϩ buffering limited volatile anesthetic inhibition of basal glutamate release. Although these results demonstrate fundamental differences in anesthetic effects on basal release between glutamatergic and GABAergic nerve terminals, all three volatile anesthetics at clinical concentrations consistently reduced the ratio of basal glutamate to GABA release. These actions may contribute to the net depression of glutamatergic excitation and potentiation of GABAergic inhibition characteristic of general anesthesia.

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Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes

Cited by 61 publications

References 37 publications

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Concentration‐dependent isoflurane effects on depolarization‐evoked glutamate and GABA outflows from mouse brain slices

Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site

Volatile Anesthetic Effects on Glutamate versus GABA Release from Isolated Rat Cortical Nerve Terminals: Basal Release

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