GABA metabolism controls inhibition efficacy in the mammalian CNS (original) (raw)
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Decrease of glutamate decarboxylase activity after in vivo cortical infusion of γ-aminobutyric acid
Neurochemistry International, 1994
Aminobutyric acid (GABA) levels and the activity of glutamate decarboxylase were measured in homogenates of rat brain cortical tissue, at different times after chronic intracortical infusion of GABA in vivo during 2, 6 or 24 h. Cortical electrical activity was also recorded. As previously described, aboul 1 h after cessation of the infusion epileptic discharges were observed (GABA-withdrawal syndrome), which lasted for several days. At zero time after cessation of the infusion, before the appearance of seizures, GABA levels were increased 3 6-fold and glutamate decarboxylase activity was decreased 2748% in the infused cortex, as compared to the contralateral cortex or to tissue from control intact rats. During epileptic discharges GABA levels gradually returned to normal values. In contrast, glutamate decarboxylase activity remained decreased during seizures and returned to normal only after recovery from the GABA-withdrawal syndrome. These results suggest that the persistent decrease in the activity of the decarboxylase is due probably to a lowered amount of the enzymatic protein, occurring as a consequence of a temporarily elevated intracellular GABA concentration. The decreased rate of GABA synthesis might be involved in the pathophysiology of the GABA-withdrawal syndrome.
Decrease of glutamate decarboxylase activity after in vivo cortical infusion of ?-aminobutyric acid
Neurochem Int, 1994
Aminobutyric acid (GABA) levels and the activity of glutamate decarboxylase were measured in homogenates of rat brain cortical tissue, at different times after chronic intracortical infusion of GABA in vivo during 2, 6 or 24 h. Cortical electrical activity was also recorded. As previously described, aboul 1 h after cessation of the infusion epileptic discharges were observed (GABA-withdrawal syndrome), which lasted for several days. At zero time after cessation of the infusion, before the appearance of seizures, GABA levels were increased 3 6-fold and glutamate decarboxylase activity was decreased 2748% in the infused cortex, as compared to the contralateral cortex or to tissue from control intact rats. During epileptic discharges GABA levels gradually returned to normal values. In contrast, glutamate decarboxylase activity remained decreased during seizures and returned to normal only after recovery from the GABA-withdrawal syndrome. These results suggest that the persistent decrease in the activity of the decarboxylase is due probably to a lowered amount of the enzymatic protein, occurring as a consequence of a temporarily elevated intracellular GABA concentration. The decreased rate of GABA synthesis might be involved in the pathophysiology of the GABA-withdrawal syndrome.
Journal of Neurochemistry, 1980
The activities of the enzymes of the GABA system, glutamate decarboxylase (GAD) and GABA-transaminase, were measured in discrete regions of the rabbit brain before the onset and during the course of sustained epileptiform seizures induced by the vitamin B, analogue methoxypyridoxine (MP). GAD activities were measured in a reaction mixture alternatively containing the cofactor pyridoxal-5'-phosphate (PLP) in excess or containing no PLP (holoenzyme of GAD). A comparison between these two estimations showed that the apoenzyme of GAD is only partially saturated with cofactor and that the degree of saturation varied from brain area to brain area, being highest in cerebellar cortex and lowest in substantia nigra. Holoenzyme activity fell steeply after administration of 100 mg/kg MP. The regional degree of enzyme inhibition by MP was a function of the saturation of the apoenzyme with cofactor; Le., a low rate of saturation resulted in a high degree of inhibition, and vice versa. That GAD from the regio inferior of the hippocampus did
European Journal of Pharmacology, 2000
. Ž . g-Aminobutyrate, a-carboxy-2-nitrobenzyl ester cGABA is a stable photoactivatable probe used to study g-aminobutyrate GABA receptors. GABA is released from this compound when it is exposed to ultraviolet light, but little is known about the electrophysiological effects of the compound itself. Whole cell patch clamp recordings on rat hippocampal slices demonstrated that cGABA blocked Ž . polysynaptic inhibitory postsynaptic currents IPSCs evoked in dentate granule cells by antidromic stimulation of the mossy fibers. It also reduced monosynaptically evoked IPSCs with an IC of 28 mM. In contrast, cGABA had no effect on excitatory postsynaptic 50 Ž . currents EPSCs evoked by perforant path stimulation. The effect of cGABA was not mediated by depression of GABA release through activation of presynaptic GABA receptors. cGABA inhibited muscimol-evoked currents by only 15% at a concentration of 40 mM. At B this same concentration, it reduced the mean frequency of miniature inhibitory postsynaptic potentials by 71%, their mean peak amplitude by 44%, their mean decay time constant by 26% and the mean charge transfer per event by 52%. These effects may be explained by a phenothiazine-like modification of GABA receptor kinetics andror a selective block of somatic GABA synapses. q 2000 Published by A Elsevier Science B.V. All rights reserved.
EFFECTS OF DI-n-PROPYLACETATE, AN ANTICONVULSIVE COMPOUND, ON GABA METABOLISM
Journal of Neurochemistry, 1969
The effects on GABA metabolism of an anticonvulsant drug, di-n-propylacetate (DPA), were studied. Given intraperitoneally DPA increases the brain GABA content and does not change its biosynthesis from glutamic acid. However, it inhibits in vitro both glutamate decarboxylase and aminobutyrate transaminase (GABA-T) activities. The inhibition is more pronounced on the GABA-T and this observation might explain the increase of GABA level.
Biochemical correlates of GABA function in rat cortical neurons in culture
Brain Research, 1980
Key words: GABA --cortical neurons --neuron cell culture --[aH]muscimol binding SUMMARY Serial biochemical studies of a rat cortical tissue culture system in which synapses regularly form showed that ),-aminobutyric acid (GABA) is present in the cultures and increases with their maturation. The tissue GABA concentration in mature cultures is similar to that of adult rat cortex in vivo. The synthetic enzyme, glutamate decarboxylase, also increases with age as does high affinity GABA uptake. GABA uptake was blocked by L-2,4-diaminobutyrate (DABA) and had the properties of neuronal GABA uptake. Specific release by depolarizing media of both exogenous [aH]GABA and GABA synthesized from D-[U-14C]glucose was demonstrated. The GABA released by high potassium media had higher specific activity and a greater contribution from glucose (as compared to acetate) than GABA found in the medium in the absence of depolarization. Calcium dependency of evoked GABA release could be shown only after pretreatment of cultures with ethyleneglycol-bis-(fl-aminoethyl ether)-N,N'-tetraacetic acid or EGTA. Synaptosomes may exhibit greater calcium dependence of evoked transmitter release than intact cells in culture because their intracellular calcium stores are depleted during preparation. Glycine uptake by the cultures was much less in amount than was GABA uptake, and specific release of glycine could not be demonstrated.
Inhibition of GABA uptake in the rat hippocampal slice
Brain Research, 1986
Pharmacological manipulations known to inhibit GABA uptake prolonged GABA-evoked conductance increases in CA1 pyramidal cells in the rat hippocampal slice preparation. Treatments included reduction of extracellular sodium and exposure to cis-4-OH-nipecotic acid, nipecotic acid or L-2,4-diaminobutyric acid (all at 1 mM). These effects contrast with the results obtained with 4-OH-isonipecotic acid, an inactive structural analog of nipecotic acid, which had no effect on the time-course of GABA responses. 4,5,6,7-Tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THPO), an impotent but selective inhibitor of GABA uptake into glia, did not prolong GABA-evoked responses. The effect of sodium reduction depended on the distance between the source of GABA and its receptors, as predicted for an uptake-limited response. GABA-receptor agonists that are poor substrates for GABA uptake (muscimol, thiomuscimol, piperidine-4-sulphonic acid, isoguvacine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP) evoked very long conductance changes that were not further prolonged by uptake inhibitors. These results demonstrate the presence of a functional GABA uptake system in the hippocampal slice. The accessibility of hippocampal GABAergic synapses and the known susceptibility of the hippocampus to epileptiform events suggest that the hippocampal slice could be a valuable CNS preparation to study the role of GABA uptake in synaptic physiology.