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PubMed1997

Benzodiazepine-GABA modulation of concurrent ethanol and sucrose reinforcement in the rat.

These experiments examined the role of the benzodiazepine (BZ)-GABA receptor complex in modulating ethanol consumption in rats. Lever presses were reinforced with concurrently available, isocaloric solutions: 10% ethanol-10% sucrose and 24% sucrose. Both reinforcers were available on independent, variable-interval 5-s schedules of reinforcement. In baseline sessions, rats earned approximately 110 sucrose reinforcers and 131 ethanol-sucrose reinforcers, equivalent to about 2 g ethanol per kilogram of body weight. Before experimental sessions, rats received injections of Ro 15-4513, Ro 15-1788, and Ro 15-4513 in combination with Ro 15-4513, chlordiazepoxide, picrotoxin, baclofen, and muscimol. Responding for the ethanol solution was significantly and selectively reduced by the BZ inverse agonist Ro 15-4513, and this effect was blocked by administration of the BZ antagonist Ro 15-1788. Conversely, responding for the ethanol solution increased following a low dose of the BZ agonist chlordiazepoxide. A low dose of baclofen significantly decreased responding for sucrose and increased consumption of ethanol. Picrotoxin and muscimol selectively reduced responding for the ethanol solution. These results are discussed in terms of the relationship between the BZ-GABA receptor complex and ethanol consumption.

Alcohol Drinking↗
PubMed1995

Two types of functionally different GABAA receptors mediate GABA modulation of cholinergic transmission in cat terminal ileum.

1. The effects of GABA (1 microM-2 mM) on longitudinally or circularly oriented organ bath preparations of cat terminal ileum consisted of a relaxation phase with an inhibition of the rhythmic spontaneous phasic contractions, followed by a phase of contractions characterized by an elevation in basal tone and an increase in amplitude of the spontaneous phasic contractions. 2. Muscimol (100 microM), but not baclofen (100 microM), mimicked the relaxation phase of the response to applied GABA (100 microM) in all tissue preparations. In addition, muscimol induced a phase of contractile activity in the circular muscle layer whilst baclofen exerted a 'GABA-like' contractile effect on the longitudinal muscle layer. Bicuculline (30 microM) or picrotoxinin (30 microM) antagonized the GABA- or muscimol-induced relaxations in all preparations and decreased the GABA- but not the baclofen-induced contractions of the longitudinal muscle layer. 3. Tetrodotoxin (0.5 microM) or atropine (0.1 microM) prevented the bicuculline-sensitive phases of the GABA or muscimol effects on both muscle layers but not the contractile effect of baclofen on the longitudinal muscle layer. 4. The bicuculline-sensitive phases of the GABA effect on both muscle layers were almost completely eliminated by 1 nM pirenzepine. At this concentration pirenzepine did not affect the electrically-evoked cholinergic twitch contractions or contractile responses to applied acetylcholine of both muscle layers. 5. During electrically-evoked cholinergic twitch contractions of both muscle layers, GABA (100 microM) had an inhibitory effect. The inhibition occurred in the presence of pirenzepine (1 nM) but not of bicuculline (30 microM). 6. It is suggested that two types of functionally different bicuculline-sensitive GABAA receptors mediate an exitatory presynaptic and an inhibitory prejunctional action of GABA on the cholinergic transmission in cat terminal ileum.

Animals↗
PubMed2001

Differences in time course of ACh and GABA modulation of excitatory synaptic potentials in slices of rat hippocampus.

Activation of muscarinic receptors and GABA(B) receptors causes presynaptic inhibition of glutamatergic synaptic potentials at excitatory feedback connections in cortical structures. These effects may regulate dynamics in cortical structures, with presynaptic inhibition allowing extrinsic afferent input to dominate during encoding, while the absence of presynaptic inhibition allows stronger excitatory feedback during retrieval or consolidation. However, proposals for a functional role of such modulatory effects strongly depend on the time course of these modulatory effects; how rapidly can they turn off and on? In brain slice preparations of hippocampal region CA1, we have explored the time course of suppression of extracellularly recorded synaptic potentials after pressure pulse application of acetylcholine and GABA. Acetylcholine causes suppression of extracellular potentials with onset time constants between 1 and 2 s, and decay constants ranging between 10 and 20 s, even with very brief injection pulses. GABA causes suppression of extracellular potentials with onset time constants between 0.2 and 0.7 s, and decay time constants that decrease to values shorter than 2 s for very brief injection pulses. These techniques do not give an exact measure of the physiological time course in vivo, but they give a notion of the relative time course of the two modulators. The slow changes due to activation of muscarinic acetylcholine receptors may alter the dynamics of cortical circuits over longer intervals (e.g., between different stages of waking and sleep), setting dynamics appropriate for encoding versus consolidation processes. The faster changes in synaptic potentials caused by GABA could cause changes within each cycle of the theta rhythm, rapidly switching between encoding and retrieval dynamics during exploration.

Acetylcholine↗
PubMed1979

GABA modulates the release of dopamine and acetylcholine from rat caudate nucleus slices.

The effects of GABA on depolarization-induced (26 mM K+) release of radiolabeled dopamine (DA) and acetylcholine (ACh) from slices of rat caudate nucleus were examined with a superfusion method. GABA, in concentrations of 10(-5)--10(-3) M, dose-dependently enhanced the release of DA, either accumulated by high-affinity uptake or synthesized from 14-C-tyrosine. In contrast, the release of ACh was reduced by GABA. This reduction appeared to be caused by the increase in DA-release. These effects of GABA decreased from the caudal to rostral part within the caudate nucleus, an order which parallels the distribution of endogenous GABA and glutamic acid decarboxylase. However, GABA had little, if any, effect in the nucleus accumbens. Since it was difficult to antagonize the effects of GABA on DA and ACh release with bicuculline or picrotoxin, it remains uncertain whether these effects were mediated via GABA receptors. In view of the high endogenous GABA level in the caudate nucleus it is concluded that GABA may be one of the local factors involved in the control of the amount of transmitter that will be released from dopaminergic varicosities upon depolarization.

Acetylcholine↗
PubMed2002

Cadmium ions modulate GABA induced currents in molluscan neurons.

The effect of Cd2+, as one of the most widespread toxic environmental pollutants, was studied on gamma-aminobutyric acid (GABA) evoked responses of identified neurons in the central nervous system of the pond snail, LYmnaea stagnalis L. (Gastropoda). In the experiments, the modulation of the action of GABA both on neuronal activity (current clamp recording) and on the a GABA activated membrane Cl- current (voltage clamp studies) has been shown. It was found that: 1. GABA could evoked three different various types of response in GABA sensitive neurons: i) hyperpolarization with strong inhibition of ongoing spike activity, ii) short depolarization with an increase of spike the activity, iii) biphasic respone with a short excitation followed by a more prolonged long inhibition. 2. In low-Cl- solution the inhibitory action of GABA was reduced or eliminated, but the excitatory one was not or only moderately affected. 3. CdCl2 inhibited the GABA evoked hyperpolarization, but left intact or only slightly reduced the excitation evoked by GABA. 4. The inward Cl- current evoked by GABA at a -75 mV holding potential was slightly augmented in the presence of I micromol/l Cd2+, but was reduced or blocked at higher cadmium concentrations. The effect of Cd2+ was concentration and time dependent. 5. Parallel with reducing the GABA evoked current, cadmium increased both the time to peak and the half inactivation time of the current. 6. CdCl2 alone, in 50 micromol/l concentration, induced a 1-2 nA inward current. The blocking effect of cadmium on GABA activated inhibitory processes can be an important component of the neuro-toxic effects of this heavy metal ion.

Animals↗
PubMed1984

GABA modulation of cholinergic transmission in rat oviduct.

The effects of electrical stimulation, gamma-aminobutyric acid (GABA), acetylcholine (ACh), norepinephrine (NE), 5-hydroxytryptamine (5-HT), GABA agonists and bicuculline were studied on spontaneous movements of isolated rat oviduct. The tissue did not respond to electrical stimulation or to GABA, NE and 5-HT when added to the incubation medium. ACh produced contractions related to its concentration which were maximal at the diestrous-1 phase when GABA caused a 20% rise in the ACh contraction. This effect was mimicked by GABA agonists whereas it was suppressed by bicuculline. beta-Estradiol benzoate (EB) increased ACh contractions in diestrous-1 and in the late proestrous phases. GABA did not modify the EB effect. Progesterone did not modify ACh contractions in any of the studied phases. These findings suggest a possible modulatory role for GABA on ACh responses in the isolated rat oviduct.

Acetylcholine↗
PubMed1983

GABA modulation of the defense reaction induced by brain electrical stimulation.

Earlier behavioral results led to the suggestion that GABA exerts a tonic inhibitory influence in the dorsal periaqueductal gray (DPAG) matter of the rat integrating defensive behavior. In the present experiments, the role of GABAergic mechanisms in the modulation of the autonomic component of the defense reaction was studied. Thus, the effects of intravenous (IV) injections of chlordiazepoxide as well as of intracerebral (IC) injections of midazolam in the dorsal midbrain, on the blood pressure (BP), heart rate (HR) and respiratory increases induced by electrical stimulation of the DPAG were measured in rats anesthetized with urethane. Chlordiazepoxide (10 mg/kg, IV) as well as midazolam (40 and 160 nmol, IC) attenuated the centrally-induced hypertension, without affecting basal BP. The tachycardia induced by aversive brain stimulation was similarly decreased by the benzodiazepines. In addition, the HR baseline was significantly raised by chlordiazepoxide and by the highest dose of midazolam. The tachypnea induced by brain electrical stimulation was also reduced by both benzodiazepines. Basal respiratory rate was slightly, but significantly decreased by chlordiazepoxide as well as by the two doses of midazolam used and to a lesser extent by the vehicle alone. Chlordiazepoxide attenuated the increase in respiratory depth caused by brain stimulation, while basal respiratory amplitude was not affected. The effects of midazolam on this parameter were unclear. Microinjection of bicuculline (5 and 10 nmol) or picrotoxin (0.3 and 1 nmol) into the DPAG increased the BP, HR and respiration, like the electrical stimulation. The latency and duration of bucuculline effects were shorter than those of picrotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

GABA modulates neurotransmission in sinus node via stimulation of GABAA receptor.

The neuromodulator role of gamma-aminobutyric acid (GABA) in the sinus node of the guinea pig heart was examined. GABA inhibited the electrical transmural stimulation (ETS)-evoked release of [3H]norepinephrine (NE) from the sinus node. Muscimol mimicked and bicuculline antagonized the inhibitory effect of GABA. However, the ETS-evoked release of [3H]NE was not inhibited by muscimol in the presence of atropine. The ETS-evoked release of [3H]acetylcholine (ACh) from the sinus node was enhanced by muscimol, and this effect was antagonized by bicuculline. As the ETS-evoked release of [3H]ACh was reduced by bicuculline alone, the endogenous GABA released by ETS is probably involved in the release of ACh. We propose that GABA, as a neuromodulator, inhibits activity of the adrenergic neuron due to stimulation of the cholinergic neuron via the GABAA receptor present in the sinus node.

Acetylcholine↗
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↗
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↗