L-DOPA-induced modulation of GABA and glutamate release in substantia nigra pars reticulata in a rodent model of Parkinson's disease.
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An autoradiographic study comparing the interactions of 3 alpha-OH-5 alpha-pregnan-20-one, pregnenolone sulfate and pentobarbital with [3S]-TBPS binding sites and their modulation by GABA in different structures of the rat brain.
Using quantitative autoradiography, we have studied the distribution of the [35S]-TBPS binding sites of the GABA-A receptor complex in various structures of the rat brain. High densities of binding sites were observed in layer IV of the cerebral cortex, in the globus pallidus, and in the thalamus. Intermediate densities of binding sites were observed in superficial and deep layers of the cerebral cortex, in the dentate gyrus and in the hippocampus. For all of these structures, the interactions of 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha 5 alpha P), pregnenolone sulfate (PS), and pentobarbital with [35S]-TBPS binding, in the presence or the absence of GABA were studied. In the absence of GABA, IC50 values for the inhibition of [35S]-TBPS binding were 10(-6) M for 3 alpha 5 alpha P and 10(-4) M for PS and pentobarbital in all of the brain regions studied. In the presence of GABA (5 x 10(-6) M), IC50 values were decreased by one order of magnitude for 3 alpha 5 alpha P, PS, and pentobarbital in all structures studied except layer IV of the cortex, where the IC50 value for PS was more markedly decreased (up to two orders of magnitude). By contrast, IC50 values for picrotoxin and TBPS to inhibit [35S]-TBPS binding were 10(-7) M and 10(-8) M, respectively, in the presence or absence of GABA.
Animals↗
Isolation and characterization of endogenous modulators for GABA system.
Pig brain extracts from both soluble and membrane fractions were found to contain potent inhibitors for GABA synthesizing enzyme, GAD, referred to as endogenous GAD inhibitors (EGIs) and for the binding of GABA agonist, muscimol, referred to as muscimol binding inhibitors (MBIs). EGIs and MBIs were first purified through gel-filtration Bio-Gel P-2 columns, in which multiple activity peaks were observed. One of them appears to be co-eluted with either L-glutamate or GABA. However, others are clearly separated from L-glutamate or GABA. EGIs were found to be low MW (less than 1,800 dalton), heat and acid-base stable, negatively charged, non hydrophobic substances. MBIs were found to be low MW (less than 1,800 dalton) neutral or positively charged substances. MBIs had no effect on [3H]flunitrazepam (FNZP) binding, indicating that they are not endogenous benzodiazepine receptor ligands and they may act specifically on GABA binding site.
Animals↗
Modulation by GABA of cholinergic transmission in the striatum.
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Acetylcholine↗
Locally evoked potentials in slices of the rat nucleus accumbens: NMDA and non-NMDA receptor mediated components and modulation by GABA.
In a slice preparation of the rat nucleus accumbens (Acb), local electrical stimulation elicited a field potential composed of two negative peaks, followed by a positive wave. The early negative peak was identified as a non-synaptic compound action potential, the late negative peak as a monosynaptic population spike (PS) and the positive wave as a mixture of an excitatory and an inhibitory postsynaptic potential (PSP). Both the PS and the PSP exhibited a marked degree of paired-pulse facilitation. The quisqualate/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 2 microM) and the broadly acting glutamate receptor antagonist kynurenic acid (300 microM) reversibly abolished or reduced both the PS and PSP. In contrast, nicotinic, muscarinic and N-methyl-D-aspartate (NMDA) receptor antagonists had no suppressive action. Washout of Mg2+ from the superfusion medium reversibly enhanced and prolonged the PSP and this effect was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5). The gamma-aminobutyric acid antagonist picrotoxin (60 microM) enhanced the PS and induced secondary spikes which were superimposed on a prolonged PSP. Most of this prolongation was abolished by D-AP-5. It is concluded that locally evoked synaptic responses in the Acb are mediated by glutamate or aspartate, and that NMDA receptor mediated activity evoked by low frequency stimulation is substantial in Mg2(+)-free medium or during reduced GABAA receptor activity, but not under normal conditions.
2-Amino-5-phosphonovalerate↗
Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo.
The effect of altering hippocampal nitric oxide (NO) levels on basal and N-methyl-D-aspartate receptor-evoked release of GABA has been studied in freely moving rats. N-Methyl-D-aspartate (NMDA) increased extracellular GABA in a concentration-dependent manner. The nitric oxide synthase inhibitor L-nitro-arginine-methyl ester (L-NAME; 100 microM) increased basal GABA release, and also enhanced release of GABA evoked by NMDA (100 microM) compared with the same concentration of NMDA infused alone. 200 microM L-NAME increased basal dialysate GABA, but to a lesser extent than the 100 microM concentration of the drug, and the NMDA-induced release of GABA was decreased. 1.0 mM L-NAME significantly decreased basal extracellular GABA, while abolishing the NMDA-evoked release of the amino acid. The actions of L-NAME were not mimicked by its much less active isomer D-nitro-arginine-methyl ester. The NO donor S-nitroso-N-acetylpenicillamine decreased dialysate GABA at a 500 microM concentration but increased the extracellular level of the transmitter when infused at 1.0 and 2.0 mM concentrations. These data suggest that NO may mediate both excitatory and inhibitory functions in vivo.
Animals↗
Modulation of GABA binding to rat brain membranes by alkyl beta-carboline-3-carboxylate esters.
The effects of the methyl, ethyl and propyl esters of beta-carboline-3-carboxylic acid were assessed on low affinity binding of GABA to rat brain membranes, and the enhancement of such binding by diazepam. The propyl ester acted as a benzodiazepine agonist in enhancing low affinity GABA binding, while the methyl and ethyl esters acted as benzodiazepine antagonists in reversing the stimulation of GABA binding by diazepam. These effects on low affinity GABA binding in vitro are consistent with pharmacological and behavioural actions of these esters in vivo and support the hypothesis that such actions are mediated via a GABA-benzodiazepine receptor complex.
Animals↗
Purified benzodiazepine receptor retains modulation by GABA.
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Animals↗
Progesterone and estrogens in rat brain: modulation of GABA (gamma-aminobutyric acid) receptor activity.
Our data indicate that estrogens and progesterone can regulate the number of GABA receptors (as detected by [3H]muscimol binding assay) in rat brain. Both hormones act in selected areas. The extent of the effect (up to 160% increase) and the number of areas responsive suggest that sex hormones may play a very important role in the regulation of the functions of GABAergic transmission in the central nervous system.
Animals↗
A physiological role for dopamine as modulator of GABA effects in substantia nigra: supersensitivity in 6-hydroxydopamine-lesioned rats.
Dopamine has been reported to attenuate the inhibitory effects of gamma-aminobutyric acid (GABA) on substantia nigra pars reticulata neurons. Five to six weeks after rats received 6-hydroxydopamine lesions of the nigral dopamine neurons, the ability of iontophoretically applied dopamine to attenuate pars reticulata responses to GABA was increased by 40% (P less than 0.05) with respect to that of unlesioned rats. These results suggest that the dopamine sites which mediate this modulatory interaction may become supersensitive in animals with dopamine-deficient nigras.
Animals↗
Neuropeptide modulation of GABA receptor C1- channels.
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Cells, Cultured↗
Anisatin modulation of GABA- and pentobarbital-induced enhancement of diazepam binding in rat brain.
Anisatin, a pure toxic substance isolated from the seeds of a Japanese plant (Illicium anisatum) acts as a picrotoxin-like, non-competitive GABA antagonist. Anisatin inhibited [3H]diazepam binding enhanced by either GABA or pentobarbital, without affecting the basal specific binding to rat brain membranes. The inhibition of this pentobarbital enhancement was competitive. These actions of anisatin were even more apparent when the binding assays were carried out at 37 degrees C rather than a 0 degrees C. Thus, at a physiological temperature, anisatin may have a more potent modulatory effect on benzodiazepine-GABA receptor coupling, through the barbiturate-picrotoxin sensitive sites.
Animals↗
gamma-Aminobutyric acidA (GABAA) receptors modulate [3H]GABA release from isolated neuronal growth cones in the rat.
Potassium-induced release of gamma-[3H]aminobutyric acid [( 3H]GABA) from a growth cone-enriched fraction isolated from neonatal rat forebrain was inhibited by the GABA mimetic muscimol in a dose-dependent manner (IC50 15 nM). The GABA antagonist bicuculline completely reversed the effect of muscimol. Bicuculline alone slightly potentiated the K+-induced release of [3H]GABA. Baclofen, a proposed selective agonist for a bicuculline-insensitive GABAB receptor, was found to cause only a slight reduction in the K+-induced release of [3H]GABA. These results are compatible with the presence of a negative feedback mechanism mediated by GABAA receptors for controlling [3H]GABA release from growth cones of the developing rat forebrain.
Animals↗
Neonatal stress and long-term modulation of GABA receptors in rat brain.
Neonatal handling, known to have long-term effects on behaviour and neuroendocrine responses to acute stress, has been found to produce a long-term change in gamma-aminobutyric acid (GABA) receptor binding (Bmax) in whole-brain membranes of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. A significant 10% increase in the binding of [3H] GABA to receptors was evident more than 100 days after handling. There were no differential effects of handling between these two strains, but there was a whole-brain deficit in GABA receptor binding in SHR as compared to WKY animals. Adult corticosterone levels did not correlate with GABA receptor binding.
Analysis of Variance↗
Modulation of GABA flux across rat brain membranes resolved by a rapid quenched incubation technique.
The progress and inhibition of [3H]GABA influx in native plasma membrane vesicles from the rat cerebral cortex was studied on a subsecond to minute time scale under different conditions by applying a rapid quenched incubation technique. In the absence of Ca2+ ([Ca2+]free = 10(-8) M), the progress of influx followed by the addition of 10 nM [3H]GABA to the membrane vesicle suspension with time (500 ms to 15 min) can be described by a first-order rate equation giving an overall rate constant, k, of 3.93 +/- 0.48 x 10(-3) s-1 and equilibrium influx value, INFe, of 8.84 +/- 0.41 pmol [3H]GABA/mg protein. In the presence of Ca2+ ([Ca2+]free = 2.4 x 10(-3) M) a significant increase in the INFe value was observed (k = 4.64 +/- 0.41 x 10(-3) s-1 and INFe = 13.9 +/- 0.40 pmol [3H]GABA/mg protein). Multiplicity of GABA transporters was indicated in the time-dependent inhibition of [3H]GABA influx by different uptake blockers. In the absence of Ca2+, depolarization (75 mM KCl) inhibited the influx of [3H]GABA into the vesicles by approximately 70% and initiated the efflux from vesicles loaded with [3H]GABA. Different uptake blockers inhibited the Ca(2+)-independent translocation of [3H]GABA in both directions with similar specificities.
Animals↗
Modulation of GABA release by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and N-methyl-D-aspartate receptors in matrix-enriched areas of the rat striatum.
Using a new in vitro superfusion device, the release of preloaded [3H]GABA was examined in microdiscs of tissues taken from sagittal slices in matrix-enriched areas of the rat striatum. Potassium (9 mM, 15 mM) stimulated the release of [3H]GABA in a concentration- and calcium-dependent manner and the veratridine (1 microM)-evoked release of [3H]GABA was completely abolished in the presence of tetrodotoxin (1 microM). The selective glutamatergic agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (1 mM) enhanced the potassium-evoked release of [3H]GABA as well as the basal outflow of [3H]GABA. This latter effect was found to be calcium-dependent, partially diminished by tetrodotoxin (1 microM), completely blocked by 6,7-dinitro-quinoxaline-2,3-dione (0.1 mM), which is generally used as an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, but not affected by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801, 10 microM), a specific antagonist of N-methyl-D-aspartate receptors. Similarly, N-methyl-D-aspartate (1 mM) enhanced both the potassium (9 mM) and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (1 mM)-evoked release of [3H]GABA but when used alone, due to the presence of magnesium in the superfusion medium, was ineffective on the basal efflux of [3H]GABA. A stimulatory effect of N-methyl-D-aspartate (1 mM) on the basal outflow of [3H]GABA was observed, however, when magnesium was omitted from the superfusion medium. The stimulatory effect of N-methyl-D-aspartate (1 mM) observed in the presence of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate was not potentiated by glycine (1 microM, in the presence of strychnine 1 microM) and the N-methyl-D-aspartate-evoked response seen in the absence of magnesium was not enhanced by D-serine (1 mM), suggesting that endogenous glycine is already acting on N-methyl-D-aspartate receptors. In fact, in the absence of magnesium, 7-chloro-kynurenate (1 mM) completely abolished the stimulatory effect of N-methyl-D-aspartate on the release of [3H]GABA confirming that under our conditions, the glycine site of the N-methyl-D-aspartate receptor is saturated. N-methyl-D-aspartate-evoked responses were all blocked by MK801 (10 microM). Finally, the N-methyl-D-aspartate-evoked response seen in the absence of magnesium was markedly reduced in the presence of tetrodotoxin (1 microM).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Interaction between allopregnanolone and pregnenolone sulfate in modulating GABA-mediated synaptic currents in neurons from the rat medial preoptic nucleus.
The two neurosteroids 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone; AlloP) and pregnenolone sulfate (PregS) affect neuronal GABA(A) receptors differently. While AlloP mainly potentiates the currents through GABA(A) receptors, PregS reduces such currents. The present study aimed at clarifying the interaction of AlloP and PregS at GABA(A) receptors in neurons from the medial preoptic nucleus of male rat. AlloP has previously been shown to dramatically prolong GABA-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in these neurons. Here, by recording sIPSCs under voltage-clamp conditions with the perforated-patch technique, it was shown that PregS by itself did not significantly affect the amplitude or time course of such currents. However, PregS, in a concentration-dependent manner, reduced the AlloP-evoked prolongation of sIPSC decay when the two neurosteroids were applied together. In contrast to sIPSC amplitude and time course, sIPSC frequency was significantly reduced by 10 microM PregS alone. Further, although 1.0 microM AlloP alone induced a clear increase in sIPSC frequency, the frequency was not significantly different from control when 1.0 microM AlloP was applied in combination with 10 microM PregS. In addition to the effects on sIPSC parameters, PregS reduced the baseline current evoked by 1.0 microM AlloP in the absence of GABA application or synaptic activity. PregS by itself did not significantly affect the baseline current. The main effects of AlloP and PregS on the sIPSC time course were mimicked by a simplified model with AlloP assumed to reduce the rate of GABA unbinding from the receptor and PregS assumed to increase the rate of desensitization.
Anesthetics↗
Modulation of GABA receptor subunits in rat facial motoneurons after axotomy.
Facial nerve axotomy is a good model for studying neuronal plasticity and regeneration in the peripheral nervous system. In the present study, we investigated the effect of axotomy on the different subunits of GABA(A) and GABA(B) receptors of facial motoneurons. The facial nerve trunk was unilaterally sectioned and operated rats were sacrificed at 1, 3, 8, 30, and 60 days later. mRNAs coding for alpha1, beta2, and gamma2 of GABA(A) receptors and for GABA(1B) and GABA(B2) receptors were down-regulated by axotomy. This decrease began as soon as 1 or 3 days after axotomy, and the minimum was 8 days post-lesion; the mRNA levels remained lower than normal at day post-lesion 60. The abundance of mRNAs coding for the three other alpha2, beta1, and beta3 facial subunits of GABA(A) receptors and for the pre-synaptic GABA(B1A) subunit remained unchanged during the period 1-8 days post-lesion. Immunohistochemistry using specific antibodies against alpha1, gamma2 subunits of GABA(A) and against GABA(B2) subunits confirmed this down-regulation. Colchicine treatment and blockade of action potential by tetrodotoxin significantly decreased GABA(A)alpha1 immunoreactivity in the axotomized facial nucleus after 7 days. Finally, muscle destruction by cardiotoxin or facial palsy induced by botulinum toxin failed to change GABA(A)alpha1 subunit expression. Our data demonstrate that axotomy strongly reduced the amounts of alpha1, beta2, and gamma2 subunits of GABA(A) receptors and B(1B) and B(2) subunits of GABA(B) receptors in the axotomized facial motoneurons. The loss of GABA(A)alpha1 subunit was most probably induced by both the loss of trophic factors transported from the periphery and a positive injury signal. It also seems to be dependent on activity disruption.
Animals↗