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PubMed2004

GABA(B) modulation of GABA(A) and glycine receptor-mediated synaptic currents in hypoglossal motoneurons.

We studied the effects of GABA(B) receptor activation on either glycine or GABA(A) receptor-mediated synaptic transmission to hypoglossal motoneurons (HMs, P8-13) using a rat brainstem slice preparation. Activation of GABA(B) receptors with baclofen, a GABA(B) receptor agonist, inhibited the amplitude of evoked glycine and GABA(A) receptor-mediated inhibitory postsynaptic currents. Additionally, with blockade of postsynaptic GABA(B) receptors baclofen decreased the frequency of both glycine and GABA(A) receptor-mediated spontaneous miniature inhibitory postsynaptic currents (mIPSCs), indicating a presynaptic site of action. Conversely, the GABA(B) receptor antagonist CGP 35348 increased the frequency of glycine receptor-mediated mIPSCs. Application of the GABA transport blocker SKF 89976A decreased the frequency of glycinergic mIPSCs. Lastly, we compared the effects of baclofen on the frequency of glycine and GABA(A) receptor-mediated mIPSC during HM development. At increased postnatal ages (P8-13 versus P1-3) mIPSC frequency was more strongly reduced by baclofen. These results show that presynaptic GABA(B) receptors inhibits glycinergic and GABAergic synaptic transmission to HMs, and the presynaptic sensitivity to baclofen is increased in P8-13 versus P1-3 HMs. Further, endogenous GABA is capable of modulating inhibitory synaptic transmission to HMs.

Animals↗
PubMed2003

Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus.

The pedunculopontine tegmental nucleus (PPTg) has an important anatomical position connecting basal ganglia and limbic systems with motor execution structures in the pons and spinal cord. It receives glutamatergic and GABAergic input and has additional reciprocal connections with mesencephalic dopaminergic neurons, suggesting that the PPTg plays a key role in frontostriatal information processing. In vivo microdialysis in freely moving rats, in combination with behavioral analysis, was used in this study to investigate whether the dopaminergic input can be modulated at the level of the PPTg via N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or GABA(B) receptors. Stimulation of the GABA(B) receptor decreased dopamine release in the PPTg while that of the AMPA and NMDA receptors increased it. A time-related comparison of the effects of NMDA (0.75 and 1 mM) and AMPA (50 and 25 microM) revealed a more long-lasting effect after AMPA stimulation than after NMDA. However, only the infusion of the GABA(B) receptor agonist baclofen (100 and 200 microM) stimulated stereotyped behavior (e.g. sniffing, digging or head movements) and contralateral circling. This study clearly demonstrates that GABAergic as well as glutamatergic terminals in the PPTg are critically involved in the modulation of the dopamine system. Moreover, a decrease in PPTg dopamine via GABA(B) receptor stimulation seems to be behaviorally relevant.

Amphetamine↗
PubMed2000

Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures.

Transplantation of genetically engineered cells can provide sustained focal delivery of naturally occurring molecules, including neurotransmitters and growth factors. We have engineered immortalized mouse cortical neurons and glia to deliver GABA by driving GAD(65) expression. Engineered cell lines showed GAD(65) mRNA expression, enzymatic activity, and GABA release. In vitro, basal flux of GABA was approximately 20% of total cellular GABA. We transplanted these GABA-producing cells bilaterally into either the anterior or the posterior substantia nigra of 43 rats. The rats were subsequently kindled through an electrode placed in the entorhinal cortex. GABA-producing cells, but not beta-galactosidase-producing cells, affected kindling rates. The number of stimulations needed to reach the first stage-5 seizure and to achieve full kindling differed significantly between the anterior and posterior transplantation sites when GAD(65)-producing cells were transplanted but not when beta-galactosidase-producing cells were transplanted. Our data show that transplanted engineered cells can make and release GABA at physiologically meaningful concentrations.

Animals↗
PubMed1998

Taurine, glutamate and GABA modulate the outgrowth from goldfish retinal explants and its concentrations are affected by the crush of the optic nerve.

The amino acid taurine plays an important trophic role during development and regeneration of the central nervous system. Other amino acid systems, such as those for glutamate and gamma-aminobutyric acid (GABA), are modified during the same physiological and pathological processes. After crushing the optic nerve, goldfish retinal explants were plated in the absence and in the presence of different amino acids and amino acid receptor agonists. The length and the density of the neurites were measured at 5 days in culture. Taurine increased the length and the density of neurites. Glutamate and glycine increased them at low concentration, but were inhibitors at higher concentration. The combination of N-methyl-D-aspartate (NMDA) and glycine produced a greater inhibitory effect than NMDA alone. NMDA or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) added simultaneously with taurine impaired the stimulatory effect of the latter. GABA stimulated the emission of neurites in a concentration dependent manner. Hypotaurine also elevated the length of neurites, but cysteinsesulfinic acid did not produce a significant effect. The concentrations of taurine, glutamate and GABA were determined by HPLC with fluorescent detection in the retina of goldfish at various days post-crushing the optic nerve. The levels of taurine were significantly increased at 48h after the crush, and were elevated up to 20 days. Glutamate level decreased after the lesion of the optic nerve and was still low at 20 days. GABA concentration was not significantly different from the control. The interaction of these amino acids during the regenerative period, especially the balance between taurine and glutamate, may be a determinant in restoring vision after the crush.

Animals↗
PubMed1987

Temperature dependence and GABA modulation of [3H]triazolam binding in the rat brain.

The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. Our major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of [3H]TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (Kd = 0.27 +/- 08 nM at 0 degree C; Kd = 1.96 +/- 0.85 nM at 37 degrees C) while the Bmax values remained unchanged (1220 +/- 176 fmoles/mg protein at 0 degree C and 1160 +/- 383 fmoles/mg protein at 37 degrees C). Saturation studies of [3H]TZ binding in the presence or absence of GABA (100 microM) showed a GABA-shift. At 0 degrees C the Kd values were (Kd = 0.24 +/- 0.03 nM/-GABA; Kd = 0.16 +/- 0.04/+GABA) and at 37 degrees C the Kd values were (Kd = 1.84 +/- 0.44 nM/-GABA; Kd = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, our findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists.

Animals↗
PubMed1998

GABA modulates cytotoxicity of immunocompetent cells expressing GABAA receptor subunits.

C57 black mouse splenic T lymphocytes effector cells were co-cultivated with Balb/c mouse splenic cells for sensitization; P815 DBA mouse mastocytoma target cells were then added and specific T cell-dependent cytotoxicity determined. This cytotoxicity increased after gamma-aminobutyric acid (GABA) treatment of the sensitized effectors, but decreased after GABA treatment of the targets. These GABA effects seemed to be specific since they were partially mimicked by linear but not ramified GABA analogues. Furthermore, they were likely mediated by GABAA receptor since GABAA receptor subunit mRNAs and protein could be demonstrated in effector or target immune specific cells, suggesting that under yet to be defined circumstances, GABA may affect T cell functions.

Animals↗
PubMed1999

Temperature dependence and GABA modulation of beta-carboline binding to rat cerebellum benzodiazepine receptors.

The temperature dependence of the binding of beta-carboline derivatives to the central benzodiazepine receptors was determined using [3H]-Ro 15-1788, as a selective radioligand. The compounds chosen display a wide spectrum of efficacies ranging from inverse agonists to agonists through antagonists. Assays were performed at 0, 10, 20, 25, 30, 35 degrees C in the absence and in the presence of 10 microM GABA. The temperature dependence of the affinity constants K(A)=1/K(D) or 1/Ki is shown in the van't Hoff plots (In K(A) versus 1/T) for each compound. Thermodynamic parameters deltaG degrees, deltaH degrees and deltaS degrees were determined by regression analysis of the plots which were linear in the range of temperatures investigated. Moreover, their slopes were systematically positive indicating that the binding of the compounds analyzed to benzodiazepine receptors is essentially enthalpy-driven both in the presence and in the absence of GABA. We verified that the ratio of affinity constant values in the presence and absence of GABA 10 microM (GABA ratio) (<1 for inverse agonists, =1 for antagonists, >1 for agonists), strongly correlates with the corresponding differences of deltaH degrees and deltaS degrees values obtained for each compound in the absence and in the presence of GABA. These results suggest that binding thermodynamic analysis of BDZ receptor ligands, in the presence and in the absence of GABA, permits to discriminate inverse agonists from antagonists, and agonists.

Animals↗
PubMed2005

GABA modulates Drosophila circadian clock neurons via GABAB receptors and decreases in calcium.

Circadian clocks play vital roles in the control of daily rhythms in physiology and behavior of animals. In Drosophila, analysis of the molecular and behavioral rhythm has shown that the master clock neurons are entrained by sensory inputs and are synchronized with other clock neurons. However, little is known about the neuronal circuits of the Drosophila circadian system and the neurotransmitters that act on the clock neurons. Here, we provide evidence for a new neuronal input pathway to the master clock neurons, s-LN(v)s, in Drosophila that utilizes GABA as a slow inhibitory neurotransmitter. We monitored intracellular calcium levels in dissociated larval s-LN(v)s with the calcium-sensitive dye Fura-2. GABA decreased intracellular calcium in the s-LN(v)s and blocked spontaneous oscillations in calcium levels. The duration of this response was dose-dependent between 1 nM and 100 microM. The response to GABA was blocked by a metabotropic GABA(B) receptor (GABA(B)-R) antagonist, CGP54626, but not by an ionotropic receptor antagonist, picrotoxin. The GABA(B)-R agonist, 3-APMPA, produced a response similar to GABA. An antiserum against one of the Drosophila GABA(B)-Rs (GABA(B)-R2) labeled the dendritic regions of the s-LN(v)s in both adults and larvae, as well as the dissociated s-LN(v)s. We found that some GABAergic processes terminate at the dendrites of the LN(v)s, as revealed by GABA immunostaining and a GABA-specific GAL4 line (GAD1-gal4). Our results suggest that the s-LN(v)s receive slow inhibitory GABAergic inputs that decrease intracellular calcium of these clock neurons and block their calcium cycling. This response is mediated by postsynaptic GABA(B) receptors.

Animals↗
PubMed1997

Opioid peptides modulate GABA(A) receptor responses in neurons of bullfrog dorsal root ganglia.

Effects of enkephalin and selective opioid-receptor agonists on GABA-induced current were examined in dissociated neurons of bullfrog dorsal root ganglia (DRG) by using whole-cell patch-clamp method. Leucine- (Leu)-enkephalin and methionine- (Met)-enkephalin depressed GABA(A) receptor-mediated currents. DPDPE, DAMGO and dynorphin-A (Dyn-A) also depressed the inward current produced by GABA; the order of agonist potency was DPDPE > DAMGO > Dyn-A. Naloxone blocked the inhibitory effects of enkephalins and other opioid agonists on the GABA current. Naltrindole (NTI), a delta-receptor antagonist, prevented the DPDPE-induced depression of the GABA current. beta-Funaltrexamine (beta-FNA), a mu-receptor antagonist, reduced the DAMGO-induced depression of GABA currents. Nor-binaltorphimine (nor-BNI), a kappa-receptor antagonist, reduced the effects of Dyn-A in depressing the GABA current. The results suggest that enkephalin down-regulates GABA(A) receptor function through mainly delta- and mu-opioid receptors in bullfrog DRG neurons.

Analgesics↗
PubMed2001

Metabotropic glutamate receptors modulate GABA release from mouse hippocampal slices.

The effects of metabotropic glutamate receptor agonists on the basal and potassium (50 mM K+)-stimulated release of [3H]GABA from mouse hippocampal slices were investigated using a superfusion system. The group I agonist (1+/-)-1-aminocyclopentane-trans-1,3-dicarboxylate enhanced the basal GABA release and reduced the K+-evoked release by a mechanism antagonized by (RS)-1-aminoindan-1,5-dicarboxylate in both cases. The group II agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine failed to have any effect on the basal release, but inhibited the stimulated release. This inhibition was not affected by the antagonist (2S)-2-ethylglutamate. The group III agonists L(+)-amino-4-phosphonobutyrate and O-phospho-L-serine inhibited the basal GABA release, which effects were blocked by the antagonist (RS)-2-cyclopropyl-4-phosphonophenylglycine. Moreover, the suppression of the K+-evoked release by L(+)2-amino-4-phosphonobutyrate was apparently receptor-mediated, being blocked by (RS)-2-cyclopropyl-4-phosphonophenylglycine. The results show that activation of metabotropic glutamate receptors of group I is able to potentiate the basal release of GABA, whereas activation of groups I and III receptors reduce K+-stimulated release in mouse hippocampal slices.

Animals↗
PubMed1989

General anesthetics modulate GABA receptor channel complex in rat dorsal root ganglion neurons.

The effects of halothane, isoflurane, and enflurane on ionic currents induced by bath application of gamma-amino-butyric acid (GABA) were studied with the rat dorsal root ganglion neurons maintained in primary culture. The whole-cell patch clamp technique was used to record the current. In normal neurons before exposure to anesthetics, GABA at low concentrations (1-3 x 10(-6) M) induced a small sustained inward current. At higher concentrations (3 x 10(-5) M-1 x 10(-3) M), GABA induced a large inward current, which decayed to a steady-state level (desensitization). Halothane (0.86 mM), isoflurane (0.96 mM), and enflurane (1.89 mM), each equivalent to the respective 2 minimum alveolar concentration (MAC) units, augmented the sustained current evoked by 3 x 10(-6) M GABA to 330-350% of control and the peak current evoked by 3 x 10(-5) M of GABA to 136-145% of control. The decay phase of the current was accelerated by the anesthetics, the time for the current to decline to 70% of the peak being reduced to 23-39% of control. In contrast, the densitized steady-state current evoked by high concentrations of GABA was decreased by anesthetics. In conclusion, general anesthetics exert a dual effect on the GABA receptor channel complex: to potentiate the nondesensitized (both peak and sustained) current and to suppress the desensitized steady-state current. The potentiation of the GABA receptor channel response may be a primary action of anesthetics leading to surgical anesthesia.

Anesthetics↗
PubMed1992

KATP channels modulate GABA release in hippocampal slices in the absence of glucose.

We studied the effects of KATP channel blockers on [3H]GABA release in the absence of glucose in rat hippocampal slices. The omission of glucose induced a marked increase in the efflux of [3H]GABA, which was antagonized by TTX (1 microM), but not by MK 801 (1 microM) or DNQX (100 microM). Glibenclamide (10-100 microM) increased dose-dependently the release of [3H]GABA evoked in the absence of glucose. An increase in [3H]GABA release was also observed with gliquidone (100-300 microM), another sulfonylurea. The potentiation of [3H]GABA release induced by glibenclamide (100 microM) was antagonized by DNQX but not by MK 801. Thus, in the absence of glucose, KATP channel blockers enhance the release of GABA from rat hippocampal slices; this effect seems to be mediated by an overstimulation of non-NMDA glutamate receptors. On the basis of results reported in the present paper, we suggest that KATP channels may play a role in the regulation of GABAergic activity during hypoglycemia.

Adenosine Triphosphate↗
PubMed1989

Baclofen and phaclofen modulate GABA release from slices of rat cerebral cortex and spinal cord but not from retina.

1. The effects of (-)-baclofen, muscimol and phaclofen on endogenous gamma-aminobutyric acid (GABA) release from rat cortical slices, spinal cord slices and entire retinas were studied. 2. The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg-1 wet wt 10 min-1. Depolarization of cortical slices with KCl (50 mM) (high-K) produced an 8 fold increase in GABA release but high-K did not evoke an increased release of GABA from spinal slices or retinas. 3. When rats were injected with gamma-vinyl-GABA (250 mg kg-1 i.p.) (GVG) 18 h before death, the tissue GABA stores were increased 3 to 6 fold and high-K then evoked striking Ca-dependent releases of GABA from all three tissues. Thus, in subsequent experiments, unless otherwise stated, the nervous tissues were taken from GVG-treated rats. 4. (-)-Baclofen (10 microM) significantly reduced the K-evoked release of GABA from cortical and spinal slices but retinal release was not affected, even at a concentration of (+/-)-baclofen of 1 mM. For cortical slices, the IC50 for baclofen was approximately 5.2 microM. The inhibitory effect of baclofen on GABA release from cortical slices also occurred in slices prepared from saline-injected rats, indicating that GVG treatment did not qualitatively affect the results. 5. The inhibitory effect of (-)-baclofen on the K-evoked release of GABA from cortical and spinal slices was antagonised by phaclofen (500 microM), confirming that baclofen was producing its effects by acting at the GABAB-receptor. 6. Phaclofen (500 microM) increased the spontaneous resting release of GABA from cortical slices taken from GVG-treated rats but not from saline-injected rats. Phaclofen did not increase GABA release from spinal slices or retinas taken from GVG-treated rats. 7. Baclofen (10 microM) significantly reduced the K-evoked release from cortical slices of glutamate, aspartate, glycine and taurine. 8. Muscimol (10 microM) and delta-aminolaevulinic acid (10 microM) had no effect on either the resting or Kevoked release of GABA from cortical slices prepared from saline-injected or GVG-treated rats. 9. The results obtained with cortical and spinal slices are consistent with the presence of inhibitory GABAB-autoreceptors. The phaclofen-induced increase in GABA release from cortical slices taken from GVG-treated rats, but not from saline-injected rats, implies that under conditions of high GABA release, considerable feedback inhibition is occurring via activation of the GABAB inhibitory autoreceptors. No evidence was found for GABAB-autoreceptors on retinal GABAergic amacrine cells or for GABAA-autoreceptors in cortical slices or spinal cord slices.

Amino Acids↗
PubMed2004

Cranial afferent glutamate heterosynaptically modulates GABA release onto second-order neurons via distinctly segregated metabotropic glutamate receptors.

The balance between excitation and inhibition dictates central integration. Glutamatergic and GABAergic neurotransmission dominate this process. Cranial primary afferents enter the brainstem to release glutamate (Glu) onto second-order neurons within the caudal nucleus tractus solitarius (NTS) to initiate autonomic reflexes. The simplest pathways for these reflexes contain as few as two central neurons, but display robust frequency-dependent behavior. Within NTS, multiple metabotropic Glu receptors (mGluRs) are present, but their roles are poorly understood. Using synaptically discriminated second-order NTS neurons in brainstem slices and mechanically dissociated NTS neurons with intact boutons, we show that Glu differentially controls GABA release via distinct presynaptic mGluRs. In second-order NTS neurons recorded in slices, activation of primary afferents at frequencies as low as 10 shocks per second released sufficient Glu to alter rates of spontaneous IPSCs (sIPSCs). In both approaches, group I mGluRs increased GABA release in some neurons, but, on different neurons, group II and group III mGluRs decreased the sIPSC rate. mGluR actions were remarkably rapid, with onset and reversal beginning within 100 msec. In all cases, mGluR actions were exclusively presynaptic, and mGluRs did not alter postsynaptic properties in second-order neurons in either slices or isolated neurons. Tests with capsaicin and alphabeta-methylene ATP suggest that myelinated and unmyelinated afferent pathways engage both mGluR-GABA mechanisms. Afferent Glu spillover provides heterosynaptic cross talk with GABAergic inhibition in NTS. This process may critically shape the dynamic character and use dependence for cranial afferent transmission at the first stage of autonomic reflexes.

Animals↗
PubMed1999

Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices.

Neuronal nicotinic receptors (nAChR) are known to control transmitter release in the CNS. Thus, this study was aimed at exploring the diversity and localization of nAChRs present in CA1 interneurons in rat hippocampal slices. The use of a U-tube as the agonist delivery system was critical for the reliable detection of nicotinic responses induced by brief exposure of the neurons to ACh or to the alpha7 nAChR-selective agonist choline. The present study demonstrated that CA1 interneurons, in addition to expressing functional alpha7 nAChRs, also express functional alpha4beta2-like nAChRs and that activation of both receptors facilitates an action potential-dependent release of GABA. Depending on the experimental condition, one of the following nicotinic responses was recorded from the interneurons by means of the patch-clamp technique: a nicotinic whole-cell current, depolarization accompanied by action potentials, or GABA-mediated postsynaptic currents (PSCs). Responses mediated by alpha7 nAChRs were short-lasting, whereas those mediated by alpha4beta2 nAChRs were long-lasting. Thus, phasic or tonic inhibition of CA1 interneurons may be achieved by selective activation of alpha7 or alpha4beta2 nAChRs, respectively. It can also be suggested that synaptic levels of choline generated by hydrolysis of ACh in vivo may be sufficient to control the activity of the alpha7 nAChRs. The finding that methyllycaconitine and dihydro-beta-erythroidine (antagonists of alpha7 and alpha4beta2 nAChRs, respectively) increased the frequency and amplitude of GABAergic PSCs suggests that there is an intrinsic cholinergic activity that sustains a basal level of nAChR activity in these interneurons.

Action Potentials↗
PubMed2003

Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABA(A) receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster.

The GABA-modulating and GABA-mimetic activities of the monoterpenoid thymol were explored on human GABAA and Drosophila melanogaster homomeric RDLac GABA receptors expressed in Xenopus laevis oocytes, voltage-clamped at -60 mV. The site of action of thymol was also investigated. Thymol, 1-100 microm, resulted in a dose-dependent potentiation of the EC20 GABA response in oocytes injected with either alpha1beta3gamma2s GABAA subunit cDNAs or the RDLac subunit RNA. At 100 microm thymol, current amplitudes in response to GABA were 416+/-72 and 715+/-85% of controls, respectively. On both receptors, thymol, 100 microm, elicited small currents in the absence of GABA. The EC50 for GABA at alpha1beta3gamma2s GABAA receptors was reduced by 50 microm thymol from 15+/-3 to 4+/-1 microm, and the Hill slope changed from 1.35+/-0.14 to 1.04+/-0.16; there was little effect on the maximum GABA response. Thymol (1-100 microm) potentiation of responses to EC20 GABA for alpha1beta1gamma2s, alpha6beta3gamma2s and alpha1beta3gamma2s human GABAA receptors was almost identical, arguing against actions at benzodiazepine or loreclezole sites. Neither flumazenil, 3-hydroxymethyl-beta-carboline (3-HMC), nor 5alpha-pregnane-3alpha, 20alpha-diol (5alpha-pregnanediol) affected thymol potentiation of the GABA response at alpha1beta3gamma2s receptors, providing evidence against actions at the benzodiazepine/beta-carboline or steroid sites. Thymol stimulated the agonist actions of pentobarbital and propofol on alpha1beta3gamma2s receptors, consistent with a mode of action distinct from that of either compound. These data suggest that thymol potentiates GABAA receptors through a previously unidentified binding site.

Allosteric Regulation↗
PubMed2006

GABA(B) receptors and synaptic modulation.

GABA(B) receptors modulate transmitter release and postsynaptic membrane potential at various types of central synapses. They function as heterodimers of two related seven-transmembrane domain receptor subunits. Trafficking, activation and signalling of GABA(B) receptors are regulated both by allosteric interactions between the subunits and by the binding of additional proteins. Recent studies have shed light on the roles of GABA(B) receptors in plasticity processes at excitatory synapses. This review summarizes our knowledge of the localization, structure and function of GABA(B) receptors in the central nervous system and their use as drug targets for neurological and psychiatric disorders.

Allosteric Regulation↗