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The influence of alpha, beta, and gamma-phenyl derivatives of gamma-aminobutyric acid (GABA) and their lactams on convulsions induced with pentetrazole, bemegride and strychnine, and with electric current, were studied. All the lactams exhibited anticonvulsant action, prolonged the latent period of action of the convulsants, and in some cases diminished mortality due to intoxication. Acid forms were devoid of anticonvulsant properties, and in some cases even potentiated convulsions.
Patients with amyotrophic lateral sclerosis have increased levels of the neutrotransmitter norepinephrine in blood and cerebrospinal fluid and depressed levels of the inhibitory neurotransmitter gamma-aminobutyric acid in cerebrospinal fluid. These neurochemical alterations are most marked in patients bedridden with advanced disease, appear interrelated, and lead to cardiovascular alterations in patients with amyotrophic lateral sclerosis.
The binding of [3H]flunitrazepam to benzodiazepine receptors in synaptic membranes and a digitonin-solubilized receptor fraction of rat brain is increased by avermectin B1a and gamma-aminobutyric acid (GABA). The effects of avermectin B1a and GABA are both sensitive to inhibition by (+)-bicuculline. Avermectin B1a and GABA both decrease the Kd and increase the Bmax of [3H]flunitrazepam binding to membranes. Kinetic analysis of the binding of [3H]flunitrazepam to rat brain membranes indicates that avermectin B1a and GABA reduce the rate constants of both association and dissociation between the ligand and the receptor. These results suggest a similar mechanism of modulation of benzodiazepine binding by avermectin B1a and GABA. This modulation may involve in interaction among the receptors for benzodiazepine, GABA and avermectin B1a.
Chronic treatment with the antidepressants imipramine or nomifensine, or the gamma-aminobutyric acid (GABAergic) agents, baclofen or THIP, produced a decrease in the Bmax for binding sites of GABAergic and noradrenergic receptors. Chronic treatment with imipramine or nomifensine produced a decrease in the Bmax of both binding of [3H]dihydroalprenolol and [3H]GABA receptors in the cerebral cortex and hippocampus. Chronic treatment with baclofen or THIP also produced a decrease in the Bmax of binding of [3H]dihydroalprenolol receptor in the cerebral cortex and hippocampus. These results suggest a possible link between the GABAergic and noradrenergic systems, which may be important in understanding the mechanism of action of antidepressant drugs, and suggests a possible role for GABA in affective disorders.
We tested the ability of the central nervous system convulsant pentylenetetrazole (PTZ) to inhibit gamma-aminobutyric acid (GABA)-gated current in receptors expressing a mutation that rendered them resistant to picrotoxin. Consistent with previous reports, receptors expressing beta2(T246F), along with alpha3 and gamma2 subunits, resulted in a greatly diminished sensitivity to picrotoxin. Sensitivity to PTZ was completely abolished in the mutant receptor, confirming the hypothesis that PTZ acts at the picrotoxin site. Quite unexpected, however, was our finding that PTZ elicited marked stimulation (up to 400% of control) in the mutated receptors. This stimulatory effect was not mediated via an interaction with the benzodiazepine site, as preincubation with the benzodiazepine antagonist flumazenil did not block the PTZ-induced stimulation. Our results reveal the existence of a novel stimulatory domain of PTZ in GABA(A) receptors.
In primary cultures of mouse cerebral cortex neurons, sulphur-containing excitatory amino acids (SAAs; namely, L-cysteine sulphinate, L-cysteate, L-homocysteine sulphinate, L-homocysteate, S-sulphocysteine) at concentrations ranging from 0.1 microM to 1 mM evoked a saturable release of gamma-[3H]aminobutyric acid ([3H]GABA) in the absence of any other depolarizing agent. All SAAs exhibited essentially similar potency (EC50, 100-150 microM) in releasing [3H]GABA although a variable profile of maximal stimulatory effect was observed when compared with basal release. The intracellular accumulation of the lipophilic cation, [3H]tetraphenylphosphonium, was significantly reduced in the presence of all SAAs, thus verifying a depolarization of the neuronal plasma membrane. SAA-stimulated release of [3H]GABA was shown to comprise two distinct components, calcium-dependent and calcium-independent, which occur after activation of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Thus, all SAA-evoked responses were antagonized by the selective, competitive NMDA-receptor antagonist, 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (IC50 range, greater than 50 microM) and the non-NMDA-receptor antagonist, 6,7-dinitroquinoxalinedione (IC50 range, 5-50 microM). Removal of magnesium ions from the superfusion medium caused a significant potentiation of SAA-evoked responses without having any effect on basal levels of [3H]GABA efflux, a result consistent with an involvement of NMDA-receptor activation. Calcium-independent release (i.e., that release remaining in the presence of 1 mM cobalt ions) was a distinct component but of smaller magnitude. Using 500 microM excitatory amino acid agonist concentrations, this component of release was (1) markedly attenuated by 15 microM SKF-89976-A, a non-transportable inhibitor of the GABA carrier, and (2) abolished when choline ions replaced sodium ions in the superfusion medium or when in the presence of excitatory amino acid receptor antagonists. These observations are clearly consistent with a receptor-mediated, depolarization-induced reversal of the GABA carrier.
The effects of propofol, a hydrophobic intravenous anaesthetic, and fentanyl, an opiate analgesic, on extracellular concentrations of gamma-aminobutyric acid (GABA) in the nucleus accumbens of rats were studied using in vivo brain microdialysis. The concentrations of GABA in the microdialysate of the nucleus accumbens reached a stable baseline value approximately 24 h after probe insertion and were not affected over the ensuing 250 min by intravenous injection of vehicle (1.0 ml/kg) or perfusion of tetrodotoxin (2 microM) into the nucleus accumbens via the dialysis membrane. Propofol (2.5 mg/kg and 10.0 mg/kg i.v.) did not significantly affect the accumbens microdialysate concentration of GABA over the 250 min of quantification. Fentanyl (100 microM) infused for 25 min into the nucleus accumbens via the dialysis membrane produced a marked and transient increase in accumbens GABA concentration to a maximum of approximately 1200% at its peak effect that occurred at 25 min after cessation of the fentanyl infusion.
Monascus, a traditional Chinese fermentation fungus, is used as a natural dietary supplement. Its metabolic products monacolin K and gamma-aminobutyric acid (GABA) have each been proven to be a cholesterol-lowering drug and a hypotensive agent. Citrinin, another secondary metabolite, is toxic to humans, thus lowering the acceptability of red mold rice to the general public. In this study, the influence of different carbon and nitrogen sources, and fatty acid or oils, on the production of monacolin K, citrinin and GABA by Monascus purpureus NTU 601 was studied. When 0.5% ethanol was added to the culture medium, the production of citrinin decreased from 813 ppb to 561 ppb while monacolin K increased from 136 mg/kg to 383 mg/kg and GABA increased from 1,060 mg/kg to 7,453 mg/kg. In addition, response surface methodology was used to optimize culture conditions for monacolin K, citrinin and GABA production, and data were collected according to a three-factor (temperature, ethanol concentration and amount of water supplemented), three-level central composite design. When 500 g rice was used as a solid substrate with 120 ml water and 0.3% ethanol, the production of monacolin K at 30 degrees C increased from 136 mg/kg to 530 mg/kg, GABA production increased from 1,060 mg/kg to 5,004 mg/kg and citrinin decreased from 813 ppb to 460 ppb.
"Desensitization" of the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied using an in vitro method for measuring chloride (Cl-) permeability in brain vesicles (synaptoneurosomes). Muscimol, a GABA agonist, stimulated 36Cl- uptake in rat cerebral cortical synaptoneurosomes in a concentration-dependent manner (EC50 7.3 +/- 0.5 microM), whereas pentobarbital stimulated 36Cl- uptake in a biphasic manner, indicated by a bell-shaped concentration-response relationship, with a maximal response at 500 microM (EC50 271 +/- 17 microM). Higher concentrations of pentobarbital led to progressively smaller stimulation of 36Cl- uptake and blocked muscimol-stimulated 36Cl- uptake. Lower concentrations of pentobarbital (100-200 microM), when added with muscimol, produced an additive effect in stimulating 36Cl- uptake, whereas even lower (subthreshold) concentrations of pentobarbital (50 microM) potentiated muscimol-stimulated 36Cl- uptake. Following continuous exposure of synaptoneurosomes (up to 20 min) to muscimol (50 microM) or pentobarbital (500 microM), the 36Cl- uptake response diminished to a new steady state level with a t1/2 of approximately 6 sec and 30 sec, respectively. The decrement in response to these agonists was dependent on both concentration and length of exposure. No decrement was observed in the ability of subthreshold concentrations of pentobarbital to enhance muscimol-stimulated 36Cl- uptake following prolonged (20 min) incubation. "Heterologous desensitization" between muscimol and pentobarbital was observed in experiments where either muscimol or pentobarbital was added to the vesicles following pretreatment with the other. These findings suggest that "desensitization" of the GABA receptor/Cl- ion channel may involve both the GABA and barbiturate recognition sites or a common effector component such as the ionophore itself.
The barrel field of the mouse somatosensory cortex (SmI) was investigated immunocytochemically using an antiserum against the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA-immunopositive cells and processes are grouped largely in the barrel side, whereas the barrel hollow is only weakly immunostained. The GABA-immunopositive cells have an ellipsoidal appearance similar to that of non-pyramidal class II barrel neurones described previously in Golgi impregnation studies of the mouse and rat barrel field.
The goal of the present study was to determine the effect of acute ethanol (ETOH), administered intraperitoneally or electro-osmotically, on norepinephrine (NE) induced increases in gamma-aminobutyric acid (GABA) mediated inhibition of single cerebellar Purkinje neurons (P-cells). Male Sprague-Dawley rats (230-370g) were anesthetized with halothane and implanted with an intraperitoneal catheter for systemic administration of ETOH (1.0-1.5 g/kg) prior to the recording session. Extracellular activity of single P-cells was recorded before and after iontophoresis of GABA and NE using five-barrel glass micropipettes. GABA was administered at the recording site by microiontophoretic pulses before, during and after continuous iontophoretic application of NE. Spontaneous discharge, GABA responses and NE-GABA interactions in P-cells were monitored for each experiment before and 1-1.5 h following systemic administration of ETOH. As in our previous reports administration of NE, at low ejection currents (10-60 nA), augmented GABA mediated suppression of P-cell spontaneous discharge. Between 10 and 60 min after injection of ETOH, this NE induced augmentation of GABA inhibition was further potentiated. This potentiation involved increases in both the magnitude and the duration of the GABA inhibition observed after NE alone. NE-induced augmentation of GABA inhibition persisted for 2-13 min longer after ETOH administration than in the pre-ETOH control period. Local electro-osmotic application of ETOH, which resulted in strong depression of spontaneous activity and caused small increases in GABA-mediated inhibition, did not directly potentiate NE-induced augmentation of GABA action. These results indicate that NE-mediated augmentation of GABA inhibition of P-cell activity is potentiated following systemic, but not local, ETOH administration.
The goal of this study was to determine whether gamma-aminobutyric acid (GABA)ergic transmission and GABA binding are altered in chronic renal-wrap hypertension. Three groups of hypertensive and sham-operated rats were prepared for separate protocols. Four weeks later, the animals were prepared with femoral artery catheters for the measurement of mean arterial pressure. In all groups, blood pressure was significantly higher in the renal-wrapped animals. In the first study, bilateral microinjection of the GABA-A antagonist, bicuculline (50 pmol/site), into the paraventricular nucleus of the hypothalamus (PVN) caused a greater increase in arterial pressure (21.9+/-1.4 versus 16.7+/-1.8 mm Hg, P<0.05) and heart rate (135+/-15 versus 98+/-12 bpm, P=0.064) in hypertensive rats. [(3)H]Flunitrazepam was used to measure binding to the GABA-A receptor. Magnocellular neurons and the adjacent medial parvicellular neurons had more intense binding compared with the remainder of the PVN. B(max) was greater for the higher density binding area; the K(d) value was less in the high-density region. There were no differences in these parameters between normotensive and hypertensive animals. Competitive reverse transcription-polymerase chain reaction was used to measure the expression of mRNA for the alpha(1) subunit of the GABA-A receptor. No difference was observed in the mRNA between renal-wrapped and sham-operated rats. In summary, inhibition of GABA-A receptors in the PVN is augmented in the chronic phase of hypertension and is unrelated to a change in the expression of the number or affinity to the receptor. These findings suggest that the greater GABAergic activity is the result of an increase in GABA release in the PVN in chronic renal-wrap hypertension.
Isolated cones dissociated from the retina of the freshwater turtle were voltage clamped using a single 'patch' pipette electrode. gamma-Aminobutyric acid (GABA) applied ionophoretically to the axon terminal evoked an inward current in cells held at -66 mV when they were recorded with patch pipettes filled with the 'control' pipette solution containing 120 mM-Cl-. Polarity of the GABA-induced current reversed near 0 mV when examined with the pipette filled with the control pipette solution. The reversal potential depended strongly on both external and intrapipette Cl- concentrations ([Cl-]o, and [Cl-]p). The reversal potential agreed with the equilibrium potential for Cl- calculated by the Nernst equation with given [Cl-]o and [Cl-]p. The reversal potential was not affected by concentrations of either external Na or K ions. Voltage responses evoked by GABA were hyperpolarizing from its resting level of about -50 mV immediately after the rupture of the patch membrane. The response polarity reversed into depolarization in a few seconds when [Cl-]p was greater than 24 mM, while hyperpolarizing responses persisted when [Cl-]p was less than 12 mM. Thus, the intracellular Cl- concentration of undisturbed isolated cones was estimated to be between 12 and 24 mM. Cones were desensitized to GABA in the presence of GABA (greater than 100 nM) in the medium, or by a prolonged ionophoretic application. The maximum reduction in response amplitude was about 70% in both experiments. Muscimol was as potent as GABA, while beta-p-chlorophenyl-GABA (baclofen) was ineffective even at 100 microM. GABA was antagonized by bicuculline competitively, and by picrotoxin non-competitively. These observations suggest that turtle cones have GABAA receptors which associate with chloride channels. The present results suggest that GABA, presumably released continuously from monophasic horizontal cells in the dark, would exert a tonic hyperpolarization in red-sensitive and green-sensitive cones. Suppression by light of tonic GABA release would depolarize these types of cones by disinhibition. Disinhibitory depolarization in cones may contribute to the centre surround antagonism in retinal neurones, and to the biphasic colour responses recorded in a subtype of horizontal cells.
6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho1 GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC(10-20) GABA responses were 22 microM, 10 microM and 6 microM and the maximum potentiations were 120%, 417% and 130% at alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha2-containing GABA(A) receptors, while sedation is thought to be mediated via alpha1-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 microM) produced positive allosteric modulation at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha2beta2gamma2L GABA(A) receptors and found to maximally potentiate the EC(10-20) GABA response by 183+/-39% which is similar to that previously observed for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha2beta2gamma2L over alpha1beta2gamma2L GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha2beta2gamma2L GABA(A) receptors, and less efficacious at alpha1beta2gamma2L GABA(A) receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors, the positive modulation of GABA responses at alpha1beta2gamma2L and alpha2beta2gamma2L GABA(A) receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via "high-affinity" benzodiazepine sites.
Neuronal cultures were made from the 8-d-old embryonic chick telencephalon. The primary culture model was further improved, the medium composition was modified, and the cells grown for 10 d, which allowed the development of relatively differentiated neurones. A superfusion protocol was developed and applied to study the release of [3H]-gamma-aminobutyric acid ([3H]GABA). High endogenous activity levels of glutamate decarboxylase (GAD) and of a Ca-dependent potassium stimulated [3H]GABA release were used as criteria for GABAergic differentiation. The influence of the non-substrate inhibitor of GABA transport, SKF 89976-A, on the GABA release, was studied using the primary neuronal culture. The release was found to be inhibited by SKF 89976-A at higher concentrations (= 400 microM).