Pharmacologically distinct GABAB receptors that mediate inhibition of GABA and glutamate release in human neocortex (original) (raw)
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British Journal of Pharmacology, 1997
1 The release of endogenous g-aminobutyric acid (GABA) and glutamic acid in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply located tumours. 2 The basal out¯ows of GABA and glutamate from superfused synaptosomes were largely increased during depolarization with 15 mM KCl. The K + -evoked over¯ows of both amino acids were almost totally dependent on the presence of Ca 2+ in the superfusion medium.
European Journal of Pharmacology: Molecular Pharmacology, 1989
Rat cerebral cortex synaptosomes prelabeled with [3H]3,-aminobutyric acid ([3H]GABA) were exposed in superfusion to various concentrations of KC1 (9-50 raM). The evoked release of [3H]GABA reached a plateau at about 35 mM KC1. The K+-induced release was Ca2+-dependent, particularly at the lowest K + concentrations. The GABA s agonist (-)-baclofen concentration dependently inhibited the release of [ 3 H]GABA evoked by K+; this effect decreased with increasing K ÷ concentration and disappeared at 35 mM KC1. The GABA A agonist muscimol (1-100 ttM) was totally ineffective to inhibit the release of [3H]GABA. Veratrine (1-30/aM) induced the release of [3H]GABA and the effect was tetrodotoxin-sensitive. (-)-Baclofen, but not muscimol, decreased the veratrine-induced [3H]GABA release; the GABA B agonist was particularly effective in presence of low concentrations of veratrine (1-3 #M) but the effect disappeared when 30 #M of the alkaloid was used. The inhibitory effect of (-)-baclofen on the release of [3 H]GABA evoked by 15 mM KCI was dependent on the concentration of Ca2+: the effect increased as the concentration of Ca 2÷ was raised, reaching a plateau at 0.6 mM Ca 2+. Exogenous GABA, in presence of the GABA uptake blocker SK&F 89976A, inhibited the release of [3H]GABA evoked by K+; this effect was antagonized by phaclofen. The data support the idea that terminal GABA autoreceptors in the rat cerebral cortex are of the GABA B type.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1981
All of the anesthetic (amylobarbitone, butobarbitone, pentobarbitone, phenobarbitone, and secobarbitone) and convulsant (5-ethyl-5(3'-methylbut-2-enyl) barbituric acid (3M2B) and 5-ethyl-5-(2'-cyclohexylidene-ethyl) barbituric acid (CHEB) barbiturates tested enhanced the binding of GABA to a carefully prepared P2 membrane fraction from rat brain in a dose-dependent manner. These findings are in agreement with the potentiation of the inhibitory effects of GABA in many neuronal systems by both classes of barbiturates.
Brain Research, 1993
The depolarization-evoked release of endogenous glutamate (GLU) and -aspartate (ASP) and its modulation mediated by y-aminobutyric acid (GABA) heteroreceptors was investigated in superfused rat cerebrocortical synaptosomes. Exposure to 12 mM K + enhanced the release of GLU and ASP. The K+-evoked overflow of both amino acids was largely Ca2+-dependent. Exogenous GABA inhibited the K+-evoked overflow of GLU (ECs0 2.8/xM) and ASP (ECs0 2.7/~M). The effect of GABA was mimicked by the GABA B receptor agonist (-)-baclofen (ECs0 2.0/zM for GLU and 1.3 /~M for ASP release) but not by the GABA A receptor agonist muscimol, up to 100 /zM. Accordingly, the GABA-induced inhibition of GLU and ASP release was not affected by the GABA A receptor antagonists, bicuculline or picrotoxin, but was antagonized by the GABA B receptor antagonist, 3-amino-propyl(diethoxymethyl)phosphinic acid (CGP 35348). The GABA effect was, however, insensitive to another GABA B receptor antagonist, phaclofen, up to 1,000 /xM. It can be concluded that GABA heteroreceptors of the GABA B type regulating the depolarization-evoked release of GLU and ASP are present on cortical GLU/ASP-releasing nerve terminals. These receptors may be classified as a phaclofen-insensitive GABA B receptor subtype.
Calcium dependent release of γ-aminobutyric acid (GABA) from human cerebral cortex
Neuroscience Letters, 1992
The release of the amino acids GABA, taurine, glycine, glutamine and leucine from human neocortex was investigated in vitro by utilizing brain tissue removed during 8 standard temporal lobectomies for epilepsy or tumor. Slices (0.5 mm thick) were cut from each biopsy and randomly placed in three different chambers. After 90 min preincubation, the three sets of slices were incubated for 60 s in wells containing, respectively, (A) regular ACSF (control), (B) ACSF with 50 mM K + (to depolarize the cell membrane) and (C) ACSF with 50 mM K +, 0 mM Ca 2. and 4 mM Mg 2÷ (depolarization during blocked synaptic transmission). The content of amino acids in the wells was determined by high-performance liquid chromatography after pre-column derivatization of the amino acids with o-phthalaldehyde. Membrane depolarization (well B) increased the GABA release to 650% (620 pmol/mg) of control (well A, 95 pmol/mg). Blocking synaptic transmission (well C) reduced the evoked release by 50% (360 pmol/mg). The release of glycine, taurine, glutamine and leucine during membrane depolarization was not significantly different from the control values. The data provide evidence for a Ca2+-dependent release of GABA, supporting a possible role of this amino acid as a neurotransmitter in human neocortex.
Journal of Neurochemistry, 2002
GABA and the GABAB receptor agonist (-)baclofen inhibited 4-aminopyridine (4AP)-and KCIevoked, Ca 2~-dependentglutamate release from rat cerebrocortical synaptosomes. The GABAB receptor antagonist CGP 35348, prevented this inhibition of glutamate release, but phaclofen had no effect. (-)-Baclofenmediated inhibition of glutamate release was insensitive to 2~tg/mlpertussis toxin. As determined by examining the mechanism of GABAB receptor modulation of glutamate release, (-)-baclofen caused a significant reduction in 4AP-evoked Ca2~influx into synaptosomes. The agonist did not alter the resting synaptosomal membrane potential or 4AP-mediated depolarization; thus, the inhibition of Ca2~influx could not be attributed to GABAB receptor activation causing a decrease in synaptosomal excitability. lonomycin-mediated glutamate release was not affected by (-)-baclofen, indicating that GABAB receptors in this preparation are not coupled directly to the exocytotic machinery. Instead, the data invoke a direct coupling of GABAB receptors to voltage-dependent Ca2c hannels linked to glutamate release. This coupling was subject to regulation by protein kinase C (PKC), because (-)-baclofen-mediated inhibition of 4AP-evoked glutamate release was reversed when PKC was stimulated with phorbol ester. This may therefore represent a mechanism by which inhibitory and facilitatory presynaptic receptor inputs interplay to fine-tune transmitter release.
Neuroscience, 1999
Use-dependent depression of inhibitory postsynaptic potentials was investigated with intracellular recordings and the paired-pulse paradigm in rat neocortical neurons in vitro. Pairs of stimuli invariably reduced the second inhibitory postsynaptic potential-A (GABA A receptor-mediated inhibitory postsynaptic potential) of a pair; at interstimulus intervals of 500 ms, the amplitude of the second inhibitory postsynaptic potential-A was considerably smaller than the first (36.2^6.2%, n17). Decreasing the interstimulus interval reduced the second inhibitory postsynaptic potential-A further and with interstimulus intervals shorter than 330 ms the compound excitatory postsynaptic potential-inhibitory postsynaptic potential response reversed from a hyperpolarizing to a depolarizing response. The depression of the inhibitory postsynaptic potential-A exhibited a maximum at interstimulus intervals near 150 ms and recovered with a time constant of 282^96.2 ms. Elimination of excitatory transmission by the application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and d(Ϫ)-2-amino-5-phosphonovaleric acid yielded an essentially unaltered time-course of paired-pulse depression (maximum depression near 150 ms, time constant of recovery 232^98 ms). The polarity change of the compound excitatory postsynaptic potential response at shorter interstimulus intervals was abolished in the presence of CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid. CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid also reduced the apparent depolarizing shift of the reversal potential between the first and second inhibitory postsynaptic potential-A from about 6 mV to less than 2 mV. Application of the GABA B receptor antagonist CGP 55845A in the presence of CNQX and d(Ϫ)-2-amino-5-phosphonovaleric acid abolished the inhibitory postsynaptic potential-B and paired-pulse depression. Under these conditions, the amplitude of the second inhibitory postsynaptic potential was, on average, about 90% of the first, i.e. reduced by about 10%. The second inhibitory postsynaptic potential-A was approximately constant at interstimulus intervals between 100 and 500 ms. It is concluded that paired-pulse depression of cortical inhibition is predominantly mediated by presynaptic GABA B receptors of GABAergic interneurons. The abolition of net inhibition at interstimulus intervals near 330 ms may facilitate spread of excitation and neuronal synchrony during repetitive cortical activation near 3 Hz. This use-dependent depression of inhibition may contribute to highly synchronized slow electroencephalogram activity during spike-and-wave or delta activity.
Anesthesiology, 1999
Background In cultured slice preparations of rat neocortical tissue, clinically relevant concentrations of volatile anesthetics mainly decreased action potential firing of neurons by enhancing gamma-aminobutyric acid (GABA(A)) receptor-mediated synaptic inhibition. The author's aim was to determine if other anesthetic agents are similarly effective in this model system and act via the same molecular mechanism. Methods The actions of various general anesthetics on the firing patterns of neocortical neurons were investigated by extracellular single-unit recordings. Results Pentobarbital, propofol, ketamine, and ethanol inhibited spontaneous action potential firing in a concentration-dependent manner. The estimated median effective concentration (EC50) values were close to or below the EC50 values for general anesthesia. Bath application of the GABA(A) antagonist bicuculline (100 microM) decreased the effectiveness of propofol, ethanol, halothane, isoflurane, enflurane, and diazepa...
Excitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1987
A newly developed continuous superfusion model was used for studies of 3H-GABA release from cultured mouse cerebral cortex neurons. It was found that a series of excitatory amino acids (EAAs) representing all receptor subtypes evoked Ca2+- dependent release of 3H-GABA from the neurons. Quisqualate was the most potent agonist tested, with an EC50 value of 75 nM. L-Glutamate, N-methyl-D-aspartate (NMDA), and kainate showed EC50 values of 12, 16 and 29 microM, respectively. The EAA-evoked 3H-GABA release could be blocked by a series of EAA antagonists. The highly selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV) was found to block NMDA responses, whereas the nonselective antagonists cis-2,3-piperidine dicarboxylic acid (PDA) and gamma-D-glutamyl-aminomethyl sulphonic acid (GAMS) blocked responses to all agonists. NMDA responses were found to be sensitive to Mg+ blockade. EAA- as well as potassium-induced 3H-GABA release from the neurons could be detected as early as d...