Dopamine-GABA interactions: evidence that GABA transmits, modulates and mediates dopaminergic functions in the basal ganglia and the limbic system.
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Amygdala↗
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[Zinc modulation of GABA receptors expressed in Xenopus oocytes injected with carp brain poly(A)+ RNA].
Two types of GABA receptors, GABAA receptors (approximately 85%) and GABAC-like receptors (approximately 15%), were expressed in Xenopus oocytes after injection of Poly(A)+ RNA with carp (Carassius carassius) brain. Using voltage-clamp technique and pharmacological methods, the effects of zinc on the two receptors were studied. It was found that zinc modulation of both GABAA and GABAC-like receptors by zinc was inhibitory and reversible with the former being stronger than the latter as indicated by a value of IC50 of 48.4 +/- 10.1 mumol/L against 255.6 +/- 21.5 mumol/L.
Animals↗
Is GABA release modulated by presynaptic excitatory amino acid receptors?
The purely GABAergic nature of spontaneous synaptic activity in cultures from the neonatal rat superior colliculus (SC) is of great advantage in investigations aimed at characterizing presynaptic factors regulating GABAergic synaptic transmission. Using SC-derived cultures it was confirmed that excitatory amino acids (EAA) can induce a marked increase in the frequency of spontaneous synaptic Cl- currents (ICl(GABA)SYN). However, this tetrodotoxin-resistant facilitation of Ca2(+)-dependent GABA release required application of EEA to several neurons (multiple cell superfusion). In contrast, no frequency increase of Icl(GABA)SYN was seen with restricted access of EAA to only one neuron and the presynaptic axonal terminals (single cell superfusion). It is therefore concluded that the strong facilitatory effect of glutamate (Glu) and kainate (KA) on GABAergic synaptic activity, as observed under the condition of multiple cell superfusion, is mediated via somatodendritic excitatory amino acid receptors (EAARs).
Action Potentials↗
Presynaptic modulation of the release of GABA by GABAA receptors in pars compacta and by GABAB receptors in pars reticulata of the rat substantia nigra.
The effect of GABA agonists and antagonists on K+-stimulated [3H]GABA release was studied to assess how presynaptic GABA receptors modulate GABA release. The release was affected in a quite different manner in the pars compacta and in the pars reticulata. Muscimol markedly inhibited the release from the pars compacta but had no effect on the release from the pars reticulata. Baclofen inhibited the release from the pars reticulata without affecting the release from the pars compacta. Bicuculline itself facilitated the release from the pars compacta but inhibited the release from the pars reticulata. Picrotoxin facilitated the release from the pars compacta and had no effect in the pars reticulata. The results suggest that the release of GABA from GABAergic terminals in the substantia nigra of the rat brain is modulated by GABAA autoreceptors in the pars compacta and by GABAB receptors in the pars reticulata.
Animals↗
Inhibition of primate spinothalamic tract neurons by spinal glycine and GABA is modulated by guanosine 3',5'-cyclic monophosphate.
Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.
Animals↗
Tonic GABA-ergic modulation of striatal dopamine release studied by in vivo microdialysis in the freely moving rat.
GABAA and GABAB receptor agonists and antagonists were administered locally in the striatum of intact and kainic acid lesioned rats. (+/-)-Baclofen, a GABAB receptor agonist, significantly decreased the level of extracellular dopamine in the striatum of intact rats. (+/-)-Phaclofen, a GABAB receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats and to a lesser extent in the striatum after kainic acid lesion. Pregnanolone (5 beta-pregnan-3 alpha-ol-20-one), a positive allosteric modulator of the GABAA receptor, significantly decreased the level of extracellular dopamine in intact rats. (-)-Bicuculline, a GABAB receptor antagonist, increased the level of extracellular dopamine in the striatum of intact rats, but failed to increase the level of extracellular dopamine after kainic acid lesion. The release of extracellular dopamine, due to infusion of phaclofen or bicuculline, was totally suppressed by tetrodotoxin. These results support a direct influence of GABA on the dopaminergic terminals via presynaptic GABAB receptors, while the effects via the GABAA receptor seem to be postsynaptic and mediated by striatal interneurons or the striatonigral feedback loop.
3,4-Dihydroxyphenylacetic Acid↗
Characterization of the metabotropic glutamate receptors (mGluRs) which modulate GABA-mediated inhibition in the ventrobasal thalamus.
The ventrobasal thalamus (VB) relays and processes somatosensory information ascending to the cerebral cortex. Several types of mGluR are known to be present in VB, and we have previously shown that Group II and Group III mGluR agonists can reduce inhibitory synaptic transmission by acting at presynaptic receptors on GABAergic terminals in this structure. We have tested the action of several antagonists against the disinhibitory action of the Group II agonist CCG-I [(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine] and the Group III agonist L-AP4 [L-2-amino-4-phosphonobutyrate] in the VB of anaesthetized rats using extracellular single-neurone recording techniques and iontophoretic applications of mGluR antagonists and agonists. The antagonists MAP4 [alpha-methyl-L-AP4] and MPPG [(+/-)-alpha-methyl-4-phosphonophenylglycine] reduced the disinhibitory actions of L-AP4 whilst having little effect on the disinhibitory action of CCG-I. In contrast, MCCG [alpha-methyl-CCG-I] and MCPG [(+)-alpha-methyl-4-carboxyphenylglycine] antagonized CCG-I, whilst having less effect against L-AP4 responses. These results support the hypothesis that GABAergic inhibitory transmission in VB can be modulated by at least two types of mGluR, belonging to Group II and Group III. Furthermore, the novel antagonists appear to be useful tools for the future study of the physiological role of these receptors in thalamic sensory processing.
Action Potentials↗
Neuroactive steroid interactions with voltage-dependent anion channels: lack of relationship to GABA(A) receptor modulation and anesthesia.
Neuroactive steroids modulate the function of gamma-aminobutyric acid type A (GABA(A)) receptors in brain; this is the presumed basis of their action as anesthetics. In a previous study using the neuroactive steroid analog, (3alpha,5beta)-6-azi-3-hydroxypregnan-20-one (6-AziP), as a photoaffinity-labeling reagent, we showed that voltage-dependent anion channel-1 (VDAC-1) was the predominant protein labeled in brain. Antisera to VDAC-1 were shown to coimmunoprecipitate GABA(A) receptors, suggesting a functional relationship between steroid binding to VDAC-1 and modulation of GABA(A) receptor function. This study examines the contribution of steroid binding to VDAC proteins to modulation of GABA(A) receptor function and anesthesia. Photolabeling of 35-kDa protein with [(3)H]6-AziP was reduced 85% in brain membranes prepared from VDAC-1-deficient mice but was unaffected by deficiency of VDAC-3. The photolabeled 35-kDa protein in membranes from VDAC-1-deficient mice was identified by two-dimensional electrophoresis and electrospray ionization-tandem mass spectrometry as VDAC-2. The absence of VDAC-1 or VDAC-3 had no effect on the ability of neuroactive steroids to modulate GABA(A) receptor function as evidenced by radioligand ([(35)S] t-butylbicyclophosphorothionate) binding or by electrophysiological studies. Electrophysiological studies also showed that neuroactive steroids modulate GABA(A) receptor function normally in VDAC-2-deficient fibroblasts transfected with alpha(1)beta(2)gamma(2) GABA(A) receptor subunits. Finally, the neuroactive steroid pregnanolone [(3alpha,5beta)-3-hydroxypregnan-20-one] produced anesthesia (loss of righting reflex) in VDAC-1- and VDAC-3-deficient mice, and there was no difference in the recovery time between the VDAC-deficient mice and wild-type controls. These data indicate that neuroactive steroid binding to VDAC-1, -2, or -3 is unlikely to mediate GABA(A) receptor modulation or anesthesia.
Anesthesia↗
Inhibitory effects of 1,4-DHP antagonists on synaptic GABA release modulated by BAY-K 8644 in mechanically dissociated rat substantia innominata.
The effects of dihydropyridine (1,4-DHP) agonist and antagonists on miniature inhibitory postsynaptic currents (mIPSCs) were investigated in mechanically dissociated rat substantia innominata neurons attached to native GABAergic presynaptic nerve terminals, namely 'synaptic bouton preparation', using nystatin perforated patch recording mode under voltage-clamp conditions. BAY-K 8644 (BAY-K), an L-type Ca(2+) channel agonist, reversibly and concentration dependently facilitated the GABAergic mIPSC frequency without altering the distribution of current amplitudes. Removal of extracellular Ca(2+) completely suppressed the facilitatory effect of BAY-K on mIPSC frequency. The facilitatory effect of BAY-K on mIPSC frequency was maintained even in the presence of selective N-, P- and Q-type Ca(2+) channel antagonists, such as 3 x 10(-6) M omega-conotoxin-GVIA (omega-CgTX-GVIA), 3 x 10(-8) M omega-agatoxin-IVA (omega-AgTX-IVA) and 3 x 10(-6)M omega-conotoxin-MVIIC (omega-CmTX-MVIIC). However, nicardipine (3 x 10(-6) M) and nimodipine (3 x 10(-6) M), 1,4-DHP antagonists, significantly inhibited the mIPSC frequency enhanced by BAY-K by 37 +/- 5 and 42 +/- 6%, respectively. These results suggest the possible existence of L-type Ca(2+) channels in GABAergic presynaptic nerve terminals.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation.
Recovery of function after acute injury to the central nervous system may be controlled by the availability of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex. Acute lesions as well as manipulation of sensory inputs can lead to rapid reorganization of the cerebral cortex, occurring within minutes to hours. Reduction of cortical inhibitory tone through a decrease in the availability of GABA has been suggested as a possible mechanism; however, the degree and temporal course of the changes in brain GABA are not known. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy showed that GABA levels in the human sensorimotor cortex are quickly reduced within minutes of deafferentation. This finding strongly supports the view that the release of latent corticocortical projections from tonic inhibition through decreased GABA availability is a mechanism of rapid cortical plasticity. Reduction of brain GABA can play a pivotal role in regulating the extent of rapid cortical reorganization after lesions or changes in sensory input.
Adult↗
On the presence of met 5-enkephalin receptors on the plasma membrane of Deiters' neurons and their modulation of GABA transport.
Met 5-enkephalin blocks the active transport of GABA across plasma membranes of rabbit Deiters' neurons prepared by microdissection. Such an effect is receptor-mediated, being reversed by the antagonist Naloxone. This result shows that Deiters' neurons bear enkephalin receptors, and suggests a hypothesis on the mechanism of enkephalin-mediated neuronal inhibition.
Animals↗
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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Animals↗
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↗