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PubMed1987

The sensitivity of gamma-aminobutyric acid antagonists to thiocyanate is related to the absence of a functional anionic group in their structure.

Pyridazinyl derivatives of gamma-aminobutyric acid (GABA) have recently been shown to be selective, reversible and competitive GABAA antagonists. Unlike what is observed with all other GABAA antagonists, the affinity of these compounds for the GABAA receptor is not modified by thiocyanate. The chemical structure of these pyridazinyl-GABA derivatives differs from that of other GABAA antagonists by the presence of a free carboxylic group in their structure. We speculated that this could explain their lack of sensitivity to thiocyanate. Consequently, we synthesized three structural analogues of these pyridazinyl-GABA derivatives in which we replaced the free carboxyl group by a cyano group. These compounds displaced [3H]GABA from rat brain membranes and reversed the GABA-induced enhancement of [3H]diazepam binding. However their affinity for the GABAA receptor increased 10- to 20-fold in the presence of thiocyanate. Thus, sensitivity to thiocyanate appears to be related more to the absence of an anionic functional group than to the agonist or antagonist nature of the GABAA ligand.

Animals↗
PubMed1995

[Collateral projections of gamma-aminobutyric acid positive neurons from the lateral superior nucleus to the cochlea and cochlear nucleus in guinea pigs].

Collateral projections of gamma-aminobutyric acid (GABA) neurons from the lateral superior olivary nucleus (LSO) to the cochlea and cochlear nuclei in the guinea pigs were studied by injection of two retrograde fluorescent neuronal tracers. For experiments, fast blue (FB) was injected into the scala tympani of one cochlea and diamidine yellow (DY) was injected into cochlear nuclei of the same side. The results showed that the FB-labelled cells and DY-labelled cells constituted approximately 80.8% and 12.4%, respectively; FB and DY double-labelled cells constituted about 6%; FB and DY labelled cells with GABA constituted about 0.7% in the ipsilateral LSO. In the contralateral LSO, the FB and DY labelled cells were less than those of ipsilateral LSO and no FB-DY double-labelled cells could be found. Our results suggest that there are collateral projections of GABA neurons from ipsilateral LSO to the organ of Corti and cochlear nuclei in the guinea pig, even though the numbers are few. The results also show that the efferent projections to the cochlea and cochlear nuclei generally come from two different auditory neuronal nuclei.

Amidines↗
PubMed1990

Two pharmacologically distinct sodium- and chloride-coupled high-affinity gamma-aminobutyric acid transporters are present in plasma membrane vesicles and reconstituted preparations from rat brain.

Electrogenic sodium- and chloride-dependent gamma-aminobutyric acid (GABA) transport in crude synaptosomal membrane vesicles is partly inhibited by saturating levels of either of the substrate analogues cis-3-aminocyclohexanecarboxylic acid (ACHC) or beta-alanine. However, both of them together potently and fully inhibit the process. Transport of beta-alanine, which exhibits an apparent Km of about 44 microM, is also electrogenic and sodium and chloride dependent and competitively inhibited by GABA with a Ki of about 3 microM. This value is very similar to the Km of 2-4 microM found for GABA transport. On the other hand, ACHC does not inhibit beta-alanine transport at all. Upon solubilization of the membrane proteins with cholate and fractionation with ammonium sulfate, a fraction is obtained which upon reconstitution into proteoliposomes exhibits 4- to 10-fold-increased GABA transport. This activity is fully inhibited by low concentrations of ACHC and is not sensitive at all to beta-alanine. GABA transport in this preparation exhibits an apparent Km of about 2.5 microM and it is competitively inhibited by ACHC (Ki approximately 7 microM). These data indicate the presence of two GABA transporter subtypes in the membrane vesicles: the A type, sensitive to ACHC, and the B type, sensitive to beta-alanine.

Animals↗
PubMed2001

Alternate cadmium exposure differentially affects the content of gamma-aminobutyric acid (GABA) and taurine within the hypothalamus, median eminence, striatum and prefrontal cortex of male rats.

This work examines changes of gamma aminobutyric acid (GABA) and taurine contents in the hypothalamus, striatum and prefrontal cortex of the rat after an alternate schedule of cadmium administration. Age-associated changes were also evaluated, of those before puberty and after adult age. In control rats GABA content decreased with age in the median eminence and in anterior, mediobasal and posterior hypothalamus, prefrontal cortex and the striatum. Taurine content showed similar results with the exception of mediobasal hypothalamus and striatum, where no changes were detected. In pubertal rats treated with cadmium from 30 to 60 days of life, GABA content significantly decreased in all brain regions except in the striatum. When cadmium was administered from day 60 to 90 of life, GABA content was significantly changed in prefrontal cortex only compared with the age matched controls. Taurine content showed similar results in pubertal rats, with the exception of the median eminence and the mediobasal hypothalamus, neither of which showed a change. However, when cadmium was administered to rats from day 60 to 90 of life, taurine content only changed in prefrontal cortex compared with the age matched controls. These results suggest that cadmium differentially affects GABA and taurine contents within the hypothalamus, median eminence, striatum and prefrontal cortex as a function of age.

Animals↗
PubMed1986

Influence of a benzodiazepine, midazolam, and gamma-aminobutyric acid (GABA) on basal somatostatin secretion from cerebral and diencephalic neurons in dispersed cell culture.

To investigate the mechanisms of gamma-aminobutyric acid (GABA) and benzodiazepine-induced growth hormone (GH) release, we studied the effects of GABA and a water-soluble benzodiazepine, midazolam, on basal immunoreactive somatostatin secretion from fetal rat brain in dispersed cell culture. Both GABA and midazolam in concentrations of 10(-5) or 10(-6) M inhibited basal somatostatin secretion from either diencephalic or cerebral neurons in culture. Midazolam (10(-5) M) produced a 33.2 +/- 8.6% suppression (P = 0.004) and 10(-5) M GABA produced a 46.0 +/- 4.3% suppression (P = 0.0003) in the diencephalon cultures. When GABA and midazolam were used in combination over the 10(-5)-10(-9) M range, the drugs were shown to act independently (positive main effect, P less than 0.0001 for either drug by two-way analysis of variance); there was a simple additive effect with no statistically significant interaction between the two drugs over the 36 combinations tested. These results suggest that suppression of the GH inhibitory peptide, somatostatin, may be one of the mechanisms by which GABA and benzodiazepines stimulate GH secretion. Based on previous studies of GABA and benzodiazepine receptors, it appears likely that these drugs produce this inhibitory effect by interacting with unassociated lower affinity receptors which require micromolar concentrations of the drugs, and act through calcium-dependent pathways.

Animals↗
PubMed1977

Glutamate decarboxylase (GAD) and gamma-aminobutyric acid (GABA) in discrete nuclei of hypothalamus and substantia nigra.

The distribution of L-glutamate decarboxylase activity (GAD) and gamma-aminobutyric acid (GABA) was investigated in the hypothalamic nuclei and in parts of the substantia nigra in the rat. GAD varied markedly among these areas. The reticular part of the nigra showed the highest activity two-fold higher than any other nucleus. Among the hypothalamic nuclei, a 5-fold difference was found between the poorest and richest nuclei. High GAD was measured in the preoptic, anterior and dorsomedial nuclei. Low activity was found in arcuate and supraoptic nuclei. The lowest GAD activity was measured in the median eminence with only half the activity of the whole brain homogenate. This suggests that GABAergic neurones might not be involved in neuroendocrine regulation at the median eminence level. GABA was determined using the sensitive cycling microassay. The rats were killed by microwaves, procedure which was found to inactivate enzymatic processes within two sec without affecting the level or the distribution of GABA. Postmortem increments during the first 3 min following decapitation ranged up to 5 times the endogenous levels, and were proportional to the GAD activity of the corresponding nucleus. This confirms that GAD is the limiting factor in GABA synthesis and suggests that GABA turnover might be rapid. Endogenous GABA showed a uniform distribution within hypothalamic nuclei and nigra. No relationship appeared between endogenous GABA levels and GAD activities in the various nuclei. These results suggest that while GABA synthesis is likely to occur in non-evenly distributed nerve cells, most GABA may be stored in surrounding cells, presumably glia cells.

Aminobutyrates↗
PubMed1986

Gamma aminobutyric acid mediates ventromedial hypothalamic mechanisms controlling the execution of lordotic responses in the female rat.

To study the participation of gamma-aminobutyric acid (GABA) in the control of sexual behavior in the female rat, the effect of GABA and picrotoxin injections in the ventromedial hypothalamic nucleus (VMN) upon lordosis frequency and multiunit spike activity (MUSA) was determined. Infusion of 100 micrograms GABA into conscious rats reduced lordotic responsiveness within 15 min after injection; with a similar time course, the same dose markedly reduced MUSA in urethane anesthetized rats. Forty-five min after injection lordotic responsiveness recuperated to preinjection levels; at this time MUSA showed a rebound increase in neuron firing frequency. The possible relation between ventromedial hypothalamic neuronal activity and capacity for lordotic responses was further tested with injections of a local anesthetic: 1 microliter of 2% Xylocaine infused into the VMN produced similar results, suppressing MUSA and lordotic responsiveness for ca. 45 min beginning immediately after injection. Microinjections of GABA antagonist picrotoxin had the opposite effects: 0.1 microgram increased MUSA and lordotic responsiveness at 5 and 45 min; however at 20 min, when MUSA was at its highest, lordosis frequency was not elevated. Injections of solvent had no consistent effects on either measure. Two conclusions many be tentatively drawn from these data: (a) the VMN is the origin of a neural signal which exerts a moment-to-moment gating control on the execution of lordosis, and (b) the generation and/or the output of this signal is under the control of a GABAergic hypothalamic mechanism which normally exerts an inhibitory effect on the display of lordotic responses.

Action Potentials↗
PubMed2006

Dietary gamma-aminobutyric acid affects the brain protein synthesis rate in young rats.

The purpose of this study was to determine whether the gamma-aminobutyric acid (GABA) affects the rate of brain protein synthesis in male rats. Two experiments were done on five or three groups of young rats (5 wk) given the diets containing 20% casein administrated 0 mg, 25 mg, 50 mg, 100 mg or 200 mg/100 g body weight GABA dissolved in saline by oral gavage for 1 day (d) (Experiment 1), and given the diets contained 0%, 0.25% or 0.5% GABA added to the 20% casein diet (Experiment 2) for 10 d. The plasma concentration of growth hormone (GH) was the highest in rats administrated 50 mg and 100 mg/100 g body weight GABA. The concentration of serum GABA increased significantly with the supplementation groups. The fractional (Ks) rates of protein synthesis in brain regions, liver and gastrocnemius muscle increased significantly with the 20% casein + 0.25% GABA diet and still more 20% casein + 0.5% GABA compared with the 20% casein diet. In brain regions, liver and gastrocnemius muscle, the RNA activity [g protein synthesized/(g RNA . d)] significantly correlated with the fractional rate of protein synthesis. The RNA concentration (mg RNA/g protein) was not related to the fractional rate of protein synthesis in any organ. Our results suggest that the treatment of GABA to young male rats are likely to increase the concentrations of plasma GH and the rate of protein synthesis in the brain, and that RNA activity is at least partly related to the fractional rate of brain protein synthesis.

Aging↗
PubMed1995

Effects of gamma-aminobutyric acid on regional vascular resistances of conscious spontaneously hypertensive rats.

1. The regional vascular effects of a central injection of gamma-aminobutyric acid (GABA) in conscious spontaneously hypertensive rats (SHR) were compared with normotensive control rats (NCR), including Wistar-Kyoto rats (male, 10-20 weeks of age). One week or more after insertion of a cannula into the cisterna magna, an electromagnetic flow probe was implanted around one of five arteries, and a catheter for measurement of blood pressure and heart rate was inserted into the terminal aorta or common carotid artery. Cardiovascular changes were observed in the conscious animal after recovery from the surgery. Peripheral resistance was calculated as pressure divided by flow. 2. Ten min following intracisternal injection of 10 mu mol of GABA, mean arterial pressure and heart rate were significantly lowered (P < 0.05; t-test): - 29 and -16% (70 d.f.) in SHR versus -23 (116 d.f.) and -19% (112 d.f.) in NCR. Hindquarters, carotid, superior mesenteric and renal, but not coeliac, vascular resistances were significantly lowered (P < 0.05; t-test, 21, 9, 18 d.f.) in SHR. However, when comparing the effect of GABA injection in SHR and NCR, there were no significant differences in coeliac, carotid and hindquarters vascular resistances, but there were significant decreases in superior mesenteric and renal vascular resistances in SHR. 3. These results indicate that: (i) a cisternal injection of GABA in SHR decreases both peripheral vascular resistance and heart rate, and thereby lowers blood pressure; (ii) the vascular resistance of the superior mesenteric and renal vascular beds was more decreased in SHR than in NCR. This suggests that the GABAergic control of regional vascular resistance differs in the SHR and the NCR.

Animals↗
PubMed1991

Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine, and gamma-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat.

We evaluated whether regional differences in the magnitude of glutamate, gamma-aminobutyric acid (GABA), and glycine release could explain why some regions are vulnerable to ischemia whereas others are spared. By means of the microdialysis technique, the temporal profile of ischemia-induced changes in extracellular levels of glutamate, GABA, and glycine was compared in regions that demonstrate differing susceptibilities to a 10- and 20-min ischemic insult (dorsal hippocampus, anterior thalamus, somatosensory cortex, and dorsolateral striatum). The degree of ischemia (as established by local cerebral blood flow reduction) and the magnitude of histopathological neuronal damage were also evaluated in these regions. The blood flow reduction was severe and uniform in all regions; however, the histopathological outcome illustrated a different pattern. Whereas the CA1 sector of the hippocampus was severely damaged, the thalamus and cortex were relatively spared from both 10 and 20 min of ischemia. Striatal neurons were resistant to a 10-min insult but severely damaged after 20 min of ischemia. Ischemia-induced increase in glutamate and GABA content were of a similar magnitude and temporal profile in all four brain regions. A uniform increase in extracellular glycine levels was also observed in all four brain structures. The postischemic response, however, was different. Glycine levels remained twofold higher than baseline in the hippocampus but fell to baseline in the cortex and thalamus after both 10- and 20-min insults. In the striatum, glycine levels returned to baseline after 10 min of ischemia but remained relatively high after a 20-min insult.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

gamma-Aminobutyric acid (GABA) immunoreactivity in mouse and rat first somatosensory (SI) cortex: description and comparison.

The location and morphological characteristics of gamma-aminobutyric acid (GABA)-immunopositive cells and their processes were studied in rat and mouse first somatosensory (SI) cortex (including 'barrels') in layer IV, and layers above (I-III), and below (V and VI). In coronal sections of SI cortex of both species GABA-immunopositive cells and punctate profiles were found in each of layers I-VI. The cells were of various sizes; the largest, located in layers III and V of each species, resemble the large basket cells seen in Golgi-impregnated material. Most of the immunopositive cells were multipolar and circular or ellipsoidal in shape, but occasionally bipolar cells with fusiform perikarya were also seen. In coronal sections, immunopositive cells did not form a characteristic pattern. GABA-immunopositive cells were observed to be most numerous in the supragranular layers whereas GABA-positive punctate profiles were more numerous in layer IV. In tangential sections from layer IV of SI cortex of both species, GABA-immunopositive cells, processes and punctate profiles were visible throughout the entire barrel field. The pattern of distribution of immunopositive cells was similar (a) in two different morphological groups--i.e. the posteromedial barrel subfield (PMBSF) and the anterolateral barrel subfield (ALBSF) in rat barrel field, and (b) in PMBSF barrels of both rat and mouse (excluding differences due to structural dissimilarities between rat and mouse barrels). GABA-immunopositive neurons were grouped mainly in the barrel side and septum and were visible frequently in small clusters. In barrels of both species GABA-immunopositive cells were of a variety of sizes and ranged in shape from ellipsoidal to circular.

Animals↗
PubMed2006

Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration.

AIMS/HYPOTHESIS: The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA(A)Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA(A)Rs in the pancreatic islets. However, the reported effects of GABA(A)R activation on insulin secretion from islet beta cells have been controversial. METHODS: This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration. RESULTS: Perforated patch-clamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 micromol/l, induced a transmembrane current (I(GABA)) which was sensitive to the GABA(A)R antagonist bicuculline. The current-voltage relationship revealed that I(GABA) reversed at -42+/-2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V (M)), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V (M) of INS-1 cells was below the I(GABA) reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V (M) of INS-1 cells was above the I(GABA) reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5). CONCLUSIONS/INTERPRETATION: These findings indicate that activation of GABA(A)Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.

Animals↗
PubMed2004

Differential expression of gamma-aminobutyric acid type B receptor subunit mRNAs in the developing nervous system and receptor coupling to adenylyl cyclase in embryonic neurons.

gamma-Aminobutyric acid type B receptors (GABA(B)Rs) mediate both slow inhibitory synaptic activity in the adult nervous system and motility signals for migrating embryonic cortical cells. Previous papers have described the expression of GABA(B)Rs in the adult brain, but the expression and functional significance of these gene products in the embryo are largely unknown. Here we examine GABA(B)R expression from rat embryonic day 10 (E10) to E18 compared with adult and ask whether embryonic cortical neurons contain functional GABA(B)R. GABA(B)R1 transcript levels greatly exceed GABA(B)R2 levels in the developing neural tube at E11, and olfactory bulb and striatum at E17 but equalize in most regions of adult nervous tissue, except for the glomerular and granule cell layers of the main olfactory bulb and the striatum. Consistent with expression differences, the binding affinity of GABA for GABA(B)Rs is significantly lower in adult striatum compared with cerebellum. Multiple lines of evidence from in situ hybridization, RNase protection, and real-time PCR demonstrate that GABA(B)R1a, GABA(B)R1b, GABA(B)R1h (a subunit subtype, lacking a sushi domain, that we have identified in embryonic rat brain), GABA(B)R2, and GABA(B)L transcript levels are not coordinately regulated. Despite the functional requirement for a heterodimer of GABA(B)R subunits, the expression of each subunit mRNA is under independent control during embryonic development, and, by E18, GABA(B)Rs are negatively coupled to adenylyl cyclase in neocortical neurons. The presence of embryonic GABA(B)R transcripts and protein and functional receptor coupling indicates potentially important roles for GABA(B)Rs in modulation of synaptic transmission in the developing embryonic nervous system.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones.

1. The ion-selective and ion transport properties of glycine receptor (GlyR) and gamma-aminobutyric acid receptor (GABAR) channels in the soma membrane of mouse spinal cord neurones were investigated using the whole-cell, cell-attached and outside-out patch versions of the patch-clamp technique. 2. Current-voltage (I-V) relations of transmitter-activated currents obtained from whole-cell measurements with 145 mM-Cl- intracellularly and extracellularly, showed outward rectification. In voltage-jump experiments, the instantaneous I-V relations were linear, and the steady-state I-V relations were rectifying outwardly indicating that the gating of GlyR and GABAR channels is voltage sensitive. 3. The reversal potential of whole-cell currents shifted 56 mV per tenfold change in internal Cl- activity indicating activation of Cl(-)-selective channels. The permeability ratio of K+ to Cl- (PK/PCl) was smaller than 0.05 for both channels. 4. The permeability sequence for large polyatomic anions was formate greater than bicarbonate greater than acetate greater than phosphate greater than propionate for GABAR channels; phosphate and propionate were not measurably permeant in GlyR channels. This indicates that open GlyR and GABAR channels have effective pore diameters of 5.2 and 5.6 A, respectively. The sequence of relative permeabilities for small anions was SCN- greater than I- greater than Br- greater than Cl- greater than F- for both channels. 5. GlyR and GABAR channels are multi-conductance-state channels. In cell-attached patches the single-channel slope conductances close to 0 mV membrane potential were 29, 18 and 10 pS for glycine, and 28, 17 and 10 pS for GABA-activated channels. The most frequently observed (main) conductance states were 29 and 17 pS for the GlyR and GABAR channel, respectively. 6. In outside-out patches with equal extracellular and intracellular concentrations of 145 mM-Cl-, the conductance states were 46, 30, 20 and 12 pS for GlyR channels and 44, 30, 19 and 12 pS for GABAR channels. The most frequently occurring main state was 46 pS for the GlyR and 30 pS for the GABAR channel. 7. Single-channel conductances measured in equal 140 mM concentrations of small anions on both membrane faces revealed a conductance sequence of Cl- greater than Br- greater than I- greater than SCN- greater than F- for both channels. This is nearly the inverse sequence of that found for the permeability of these ions indicating the presence of binding sites for ions in the channel.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1988

Inactivation of gamma-aminobutyric acid aminotransferase by (Z)-4-amino-2-fluorobut-2-enoic acid.

(Z)-4-Amino-2-fluorobut-2-enoic acid (1) is shown to be a mechanism-based inactivator of pig brain gamma-aminobutyric acid aminotransferase. Approximately 750 inactivator molecules are consumed prior to complete enzyme inactivation. Concurrent with enzyme inactivation is the release of 708 +/- 79 fluoride ions; transamination occurs 737 +/- 15 times per inactivation event. Inactivation of [3H]pyridoxal 5'-phosphate ([3H]PLP) reconstituted GABA aminotransferase by 1 followed by denaturation releases [3H]PMP with no radioactivity remaining attached to the protein. A similar experiment carried out with 4-amino-5-fluoropent-2-enoic acid [Silverman, R. B., Invergo, B. J., & Mathew, J. (1986) J. Med. Chem. 29, 1840-1846] as the inactivator produces no [3H]PMP; rather, another radioactive species is released. These results support an inactivation mechanism for 1 that involves normal catalytic isomerization followed by active site nucleophilic attack on the activated Michael acceptor. A general hypothesis for predicting the inactivation mechanism (Michael addition vs enamine addition) of GABA aminotransferase inactivators is proposed.

4-Aminobutyrate Transaminase↗
PubMed1975

Tetramethylenedisulphotetramine: an inhibitor of gamma-aminobutyric acid induced depolarization of the isolated superior cervical ganglion of the rat.

Tetramethylenedisulphotetramine (TETS), a potent convulsant, antagonized the depolarizing action gamma-aminobutyric acid (GABA) in the isolated superior cervical ganglion of the rat. No antagonism of responses to the cholinomimetic agent carbachol was observed. TETS appeared to act in a non-competitive manner and was reversible. Its activity profile was comparable to that of bicuculline in the same tissue except that the latter appears to act in a competitive manner.

Aminobutyrates↗
PubMed1995

Simultaneous monitoring of the seizure-related changes in extracellular glutamate and gamma-aminobutyric acid concentration in bilateral hippocampi following development of amygdaloid kindling.

We simultaneously monitored the seizure-related changes in extracellular hippocampal glutamate (Glu) and gamma-aminobutyric acid (GABA) concentration in brain dialysates in order to clarify the role of Glu and GABA in the development of kindling. Brain dialysates were collected every 5 min from 10 min prior to 80 min after stimulus in the three developing conditions consisting of pre-kindling state, stage 3 (C-3), and five consecutive stage 5 (5*C-5) following kindling in the same rat. Extracellular Glu level increased rapidly, lasting for only 5 min after stimulus. The post-stimulus ratio of Glu increase in partially kindled rats (C-3) was 2.5-3.5 times of the baseline, and in fully kindled rats it was about 5 times of the baseline. Extracellular GABA concentration enhanced gradually, reaching a plateau level at 15-20 min and lasting for several hours after stimulus at each stage. The enhancement of GABA level was about 1.5 times of the baseline in partially kindled stage, and was about 2.5 times of the baseline in fully kindled stage. There was no significant difference between the two hemispheres with respect to either the time-course or the magnitude of Glu and GABA increase respectively. These data show that progressive, transient and stimulus-induced enhancement of extracellular Glu levels combined with long-lasting elevation of extracellular GABA levels in the bilateral ventral hippocampi results in imbalance between the excitatory and inhibitory neuronal systems, causing excessive propagation of seizure activity, culminating in the secondary generalized seizure of amygdaloid kindling.

Amygdala↗