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At least 19 recordsLinked to original sources

PubMed1992

Evidence for a modulation of human chorionic gonadotropin (hCG) subunit messenger ribonucleic acid levels and hCG secretion by gamma-aminobutyric acid in human first trimester placenta in vitro.

The cytotrophoblasts are the site of production of liberins and statins in human placenta, whereas the syncytiotrophoblasts synthesize tropic hormones. These placental cell layers seem to interact like the hypothalamus and pituitary. In the central nervous system, gamma-aminobutyric acid (GABA)-ergic neurons represent one important control mechanism that seems to influence the lutropin biosynthesis indirectly (via gonadoliberin) and directly. It was the objective of the present study to find out whether GABA also may influence the biosynthesis and secretion of hCG by human first trimester placenta. Already one single pulse of GABA (1 h; 0.01-100 microM) stimulated hCG secretion significantly (P less than 0.0001). GABA also induced a marked increase in the mRNA levels of both subunits, with an optimum at 10 microM. The effect on hCG secretion was mimicked by the GABA-A receptor agonist muscimol (P less than 0.002), but under the experimental conditions used (multiple pulses; 1 microM), only the beta mRNA was increased. The GABA-A receptor antagonist bicuculline (two pulses; 10 microM) suppressed basal hCG secretion (P less than 0.001) and abolished the episodic secretion pattern observed in the control cultures. Applying a combination of equimolar amounts of GABA and bicuculline, hCG secretion and the episodic secretion pattern were similar as in control cultures. The data seem to suggest a regulation of hCG biosynthesis in human first trimester placenta in which GABA is involved, probably acting via GABA-A-like receptor sites.

Bicuculline↗

PubMed1992

The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum.

In an effort to determine subunit compositions of in vivo GABAA receptors, the cellular localization of 13 subunit encoding mRNAs (alpha 1-alpha 6, beta 1-beta 3, gamma 2-gamma 3, delta) was determined in the rat olfactory bulb and cerebellum. Cerebellar granule cells expressed significant quantities of alpha 1, alpha 6, beta 2, beta 3, gamma 2, and delta mRNAs. They contained very much lower levels of alpha 4, beta 1, and gamma 3 mRNAs, and the alpha 2, alpha 3, alpha 5, and gamma 1 genes appeared to be silent. Purkinje cells contained only the alpha 1, beta 2, beta 3, and gamma 2 mRNAs. Putative Bergmann glial cells were found to contain the gamma 1 mRNA and possibly the alpha 2 mRNA. In the molecular layer, only the alpha 1, beta 2 and gamma 2 mRNAs were expressed in stellate/basket cells. The alpha 3 probe hybridized weakly to targets in the molecular layer. The inferior olivary nucleus contained significant quantities of alpha 2, alpha 4, and gamma 1 transcripts, with the alpha 1, alpha 3, beta 2, beta 3, and gamma 2 mRNAs also present. In the olfactory bulb, mitral cells were found to express the alpha 1, beta 1, beta 2, beta 3, and gamma 2 mRNAs strongly and the alpha 3 mRNA weakly. Tufted cells contained alpha 1, alpha 3, beta 2, beta 3, and gamma 2 mRNAs and, occasionally, the alpha 2 mRNA. In the internal granule cells the alpha 2, alpha 4, alpha 5, beta 3, and delta mRNAs were all present. Low levels of alpha 3, gamma 1, gamma 2, and gamma 3 mRNAs were also noted in these cells. Periglomerular cells expressed low levels of alpha 2, alpha 3, alpha 4, beta 2, beta 3, gamma 1, gamma 2, and gamma 3 mRNAs. No alpha 6 mRNA was present in the olfactory bulb. Correlations that are general ones from other brain regions are the colocalizations of alpha 1 beta 2, alpha 2 beta 3, and alpha 4 delta mRNAs. In both the olfactory bulb and cerebellum, alpha 1 beta 2 gamma 2 receptor cores are probably employed. The delta-subunit mRNA appears to codistribute with alpha-subunit mRNAs (alpha 4 and alpha 6) associated with GABAA subunits that fail to bind benzodiazepine agonists.

Animals↗

PubMed1992

Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogues of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones at benzodiazepine receptors.

Based on the topology of pyrazoloquinolinones 10-12, a series of 2-phenyl-2H-pyrazolo[4,3-c]isoquinolines 6a-d, 7a-d, 8, and 9 have been synthesized and evaluated for their ability to inhibit radioligand binding to benzodiazepine receptors (BzR). Modification of the hydrogen bonding donor and acceptor characteristics of the NH and C = O functionalities of the pyrazoloquinolinones 10-12 resulted in ligands with dramatically reduced affinities (IC50 much greater than 2 microM) for BzR. The low affinities of 6a-d, 7a-d, 8, and 9 are consistent with the involvement of the NH function present on diverse classes of inverse agonists (beta-carbolines, diindoles, and pyrazoloquinolinones) with a hydrogen bond acceptor site (A2) on the binding protein. Moreover, it supports the involvement of the carbonyl function of the pyrazoloquinolinones and the pyridine nitrogen atom of beta-carbolines and diindoles with a hydrogen bond donor site (H1). Finally, the results from this work indicate that a simultaneous interaction at both hydrogen bond donor (H1) and acceptor sites (A2) at BzR is required for high affinity binding of inverse agonists.

Animals↗

PubMed1992

Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists: stereostructure-activity relationships.

The (R) and (S) forms of 5-amino-2-hydroxyvaleric acid (2-OH-DAVA) and 5-amino-4-hydroxyvaleric acid (4-OH-DAVA) were designed as structural hybrids of the 4-aminobutyric acidB (GABAB) agonist (R)-(-)-4-amino-3-hydroxybutyric acid [(R)-(-)-3-OH-GABA] and the GABAB antagonist 5-aminovaleric acid (DAVA). (S)-(-)-2-OH-DAVA and (R)-(-)-4-OH-DAVA showed a moderately potent affinity for GABAB receptor sites in rat brain and showed GABAB antagonist effects in a guinea pig ileum preparation. The respective enantiomers, (R)-(+)-2-OH-DAVA and (S)-(+)-4-OH-DAVA, were markedly weaker in both test systems. All four compounds were weak inhibitors of GABAA receptor binding in rat brain, and none of them significantly affected synaptosomal GABA uptake. Based on molecular modeling studies it has been demonstrated that low-energy conformations of (R)-(-)-3-OH-GABA, (S)-(-)-2-OH-DAVA, and (R)-(-)-4-OH-DAVA can be superimposed. These conformations may reflect the shapes adopted by these conformationally flexible compounds during their interaction with GABAB receptors. The present studies emphasize the similar, but distinct, constraints imposed on agonists and antagonists for GABAB receptors.

Amino Acids↗

PubMed1992

The third gamma subunit of the gamma-aminobutyric acid type A receptor family.

Cloned cDNAs encoding a member of the gamma-aminobutyric acid type A receptor gamma-subunit class were isolated from rat-brain-mRNA-derived libraries. The gamma 3 mRNA is present in cortex, claustrum, caudate putamen, and some thalamic nuclei, particularly the medial geniculate nucleus, where it is the predominant gamma-subunit transcript. The gamma 3 gene is expressed at very low levels in cerebellum and hippocampus. In coexpression experiments with the alpha 1 and beta 2 subunits, gamma 3 imparts benzodiazepine binding to gamma-aminobutyric acid type A receptors and forms gamma-aminobutyric acid-gated benzodiazepine-modulated chloride channels that exhibit a larger conductance than alpha 1 beta 2 receptor channels. Furthermore, the presence of gamma 3 in place of gamma 2 in alpha 1 beta 2 gamma x receptors generates a marked decrease in the affinity of agonists while leaving the affinity of antagonists or negative modulators largely unaffected.

Amino Acid Sequence↗

PubMed1992

Beta-proline analogues as agonists at the strychnine-sensitive glycine receptor.

3-Carboxy-3,4-dehydropyrrolidine was found to bind with affinity equal to that of glycine in a [3H]strychnine binding assay. Simple substitution of the 1-, 2-, 4-, or 5-position resulted in marked loss of affinity. A decline in affinity was also found upon enlargement, contraction, or saturation of the 5-membered ring. However, beta-proline and azetidine-3-carboxylic acid retained significant binding affinity. Despite its good affinity in [3H]strychnine binding, 3-carboxy-3,4-dehydropyrrolidine showed only weak agonist activity in intracellular recordings of cultured murine spinal cord neurons. This apparent lack of correlation between binding and functional results is discussed in light of the current models of the strychnine-sensitive glycine receptor.

Animals↗

PubMedDate not supplied

The role of GABA-ergic signal in the regulation of melatonin biosynthesis in vertebrate retina.

The in vivo effects of GABA-ergic drugs on the activity of serotonin N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), two enzymes involved in melatonin biosynthesis, were investigated in light-exposed chicken retina. The ip administration of muscimol and baclofen (direct agonists of GABA-A and GABA-B receptors, respectively), aminooxyacetic acid (an inhibitor of GABA transaminase), and nipecotic acid (an inhibitor of GABA reuptake), significantly increased the retinal NAT activity by 50-100%. Similar rises in NAT activity were observed following intraocular treatment of ether-anesthetized chickens with muscimol, baclofen and GABA. In contrast to NAT, there was no effect of the tested drugs on the retinal HIOMT activity. Aminophylline (a phosphodiesterase inhibitor) markedly elevated the retinal NAT activity, and a combined treatment with the GABA-ergic drugs and aminophylline resulted in additive effects. The actions of both muscimol and baclofen were antagonized by picrotoxin and bicuculline (two GABA-A receptor blockers), whereas the effect of baclofen was not changed by a selective GABA-B receptor blocker, CGP 35,348. Melatonin given ip significantly raised NAT activity, and its combination with muscimol further stimulated the enzyme. Picrotoxin and bicuculline given to chickens during the dark phase of 12 h light--12 h dark illumination cycle significantly suppressed the nocturnal NAT activity in retina. Neither GABA nor muscimol and baclofen significantly affected basal and forskolin (1 microM)-stimulated adenylate cyclase activity in vitro in light-exposed chicken retina. It is concluded that a GABA signal (acting through type A of GABA receptors) plays an important role in a complex mechanism regulating the rhythmic melatonin biosynthesis in vertebrate retina.

Acetylserotonin O-Methyltransferase↗

PubMed1992

In vivo characterization of the pharmacodynamic interaction of a benzodiazepine agonist and antagonist: midazolam and flumazenil.

The pharmacokinetic and pharmacodynamic interaction between the benzodiazepine agonist midazolam and antagonist flumazenil was quantified in vivo in rats, using effect parameters derived from aperiodic EEG analysis. The benzodiazepine-induced increase in amplitudes in the 11.5 to 30 Hz (beta) frequency band of the EEG was used as effect measure. A competitive interaction model was derived that could describe and predict the time course of EEG effect after administration of several combinations of midazolam and flumazenil. Two approaches to derive the interaction model were evaluated. In a first experiment, rats received 10 or 20 mg/kg midazolam i.v. in 15 min during a steady-state infusion of flumazenil at a rate of 0, 0.25, 0.5 or 1 mg/kg/hr. The EEG was continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. Flumazenil did not influence the pharmacokinetics of midazolam, but a significant reduction in the clearance of flumazenil was observed in the presence of midazolam. Flumazenil did not possess any intrinsic efficacy with regard to the EEG effect measure. With increasing flumazenil concentrations, a parallel shift in the concentration-EEG effect relationship of midazolam was observed, confirming the competitive nature of the interaction. An agonist-antagonist interaction model was used to quantify the interaction, yielding the pharmacodynamic parameters of midazolam [(mean +/- S.E.): Emax = 80 +/- 5 microV/sec, EC50 = 35 +/- 3 ng/ml and N = 1.1 +/- 0.2] and flumazenil: EC50 = 24 +/- 2 ng/ml and N = 1.6 +/- 0.1. In a second experiment, rats received 5 mg/kg flumazenil or placebo i.v. in 10 min during a steadystate infusion of midazolam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Quantitative immunoprecipitation studies with anti-gamma-aminobutyric acidA receptor gamma 2 1-15 Cys antibodies.

Antibodies raised against the synthetic peptide NH2-QKSDDDYEDYASNKTC-COOH (gamma 2 1-15 Cys), which corresponds to the N-terminal amino acid sequence with a C-terminal cysteine of the human gamma 2 subunit of the gamma-aminobutyric acidA (GABAA) receptor, were used to study the quantitative immunoprecipitation of agonist benzodiazepine binding sites from bovine brain. Anti-gamma 2 1-15 Cys antibodies were found to immunoprecipitate specifically in parallel [3H]flunitrazepam- and [3H]muscimol-reversible binding sites in a dose-dependent manner. The maximum percentages of [3H]flunitrazepam binding sites immunoprecipitated from detergent extracts of bovine cerebral cortex, cerebellum, and hippocampus were 68, 77, and 83%, respectively. Immunoprecipitation studies with anti-alpha 1 324-341 antibodies carried out in parallel with anti-gamma 2 1-15 Cys antibodies provided evidence for the promiscuity of the gamma 2 subunit within native GABAA receptors. These results substantiate the association of the gamma 2 polypeptide with native GABAA receptors.

Amino Acid Sequence↗

PubMed1992

Thyrotropin-releasing hormone selectively reverses lorazepam-induced sedation but not slowing of saccadic eye movements.

To investigate preliminary reports that benzodiazepine-induced sedation may be reversed by thyrotropin-releasing hormone (TRH), we examined the effect of TRH or saline placebo on two variables which are sensitive to benzodiazepine agonists: changes in sedation and saccadic eye movements. Lorazepam 10 micrograms/kg i.v. increased self-ratings of sedation and reduced self-ratings of alertness and these changes were almost completely reversed by TRH. In contrast the slowing of saccadic eye movements by lorazepam was not reversed by TRH. The effects of TRH do not appear to be due to a direct antagonism at the benzodiazepine receptor, since flumazenil reverses changes in both variables. Moreover ligand binding studies reveal that TRH has very low affinity at this receptor. These clinical data provide the first demonstration that it is possible to distinguish between the effects of benzodiazepines on saccadic eye movements and psychological self-ratings.

Adult↗

PubMed1992

The effect of systemic administration of baclofen on food intake in rats.

The effects of systemic administration of the GABAB agonist, baclofen was investigated on food intake in non-fasted rats. Baclofen (1.0, 2.0 and 4.0 mg/kg, s.c.) produced a dose-related increase in food intake in a free-feeding paradigm during the first 90 min after administration, with maximum increases occurring at a dose of 2 mg/kg (Experiment 1). Baclofen (0.5 and 1.0 mg/kg, s.c.) also increased food intake in the 40 min post-drug recording period in non-fasted rats, trained to make operant responses for food on a fixed-ratio schedule (Experiment 2). These results demonstrate that systemic administration of baclofen can stimulate ingestive behaviour in satiated rats and suggest a possible role for a GABAB receptor-mediated mechanism in the control of food intake.

Animals↗

PubMed1992

gamma-Aminobutyric acid receptor activation of outer hair cells in the guinea pig cochlea.

Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter of the central nervous system, may also be released from olivocochlear efferent nerves reaching the outer hair cells of the cochlea. In the present study the cell potential of isolated outer hair cells of the third and fourth turns of the guinea pig cochlea was measured with patch-clamp electrodes. GABA-receptor agonists and antagonists were applied extracellularly. The cell membrane hyperpolarized in a reversible manner with increasing concentrations of extracellular GABA. Half-maximal hyperpolarization (2 mV) was achieved with approximately 10(-7) M GABA. Desensitization was not observed. The hyperpolarizing effect of GABA was potentiated by the benzodiazepine clorazepate and was blocked by picrotoxin.

Animals↗

PubMed1992

Ethanol modulation of GABA receptor-activated Cl- currents in neurons of the chick, rat and mouse central nervous system.

Modulation of gamma-aminobutyric acidA (GABAA) receptor function by drugs such as ethanol may depend on the genetic heterogeneity of GABAA receptor subunits, which vary across species and cell types. For this reason, the effects of ethanol on gamma-aminobutyric acid receptor-activated chloride currents (IGABA) were examined using whole-cell voltage-clamp recordings in primary cultures of neurons obtained from different species (chick, mouse and rat) and from different brain regions (cerebral cortex, hippocampus, cerebellum and spinal cord), and in acutely dissociated neurons from rat neocortical slices. Low concentrations (1-50 mM) of ethanol produced an enhancement of IGABA in some cells from each brain region examined. In cells obtained from the rat and chick cerebral cortex, 40-58% of cells exhibited an ethanol-sensitive IGABA. Moreover, a statistically significant variation in the response to ethanol was found in rat cortical neurons obtained from different litters. In mouse hippocampal neurons, potentiation of IGABA was obtained with ethanol concentrations (1-10 mM) well below those needed to inhibit neuronal responses to N-methyl-D-aspartic acid (30-50 mM), suggesting a differential sensitivity of these two receptor mechanisms to ethanol. Potentiation of IGABA by ethanol was reversed by the benzodiazepine receptor partial inverse agonist RO15-4513 (ethyl 8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine - 3-carboxylate), but was not affected by chelation of intracellular calcium. Furthermore, high concentrations of GABA attenuated the ability of ethanol to enhance IGABA. These results are consistent with the hypothesis that ethanol facilitates coupling between receptor binding and chloride channel activation.

Animals↗

PubMed1992

Effects of GABA receptor stimulation on the release of [3H]GABA from slices of rat neostriatum.

Slices of rat neostriatum were incubated in Krebs-Henseleit medium. Modulation of [3H]GABA release by GABA agonists and antagonists was investigated. The GABAA receptor agonists muscimol (0.1 microM) and isoguvacine (5 microM) enhanced the stimulated release of [3H]GABA. The antagonists picrotoxin (1 microM) and bicuculline (50 microM) prevented the effects of the agonists. In the presence of naloxone (1 microM), which blocked the effects of enkephalinergic neurons within the slice preparation, muscimol (1 microM) no longer affected the release of [3H]GABA.

Animals↗

PubMed1992

Primary receptor for inhibitory transmitters in lamprey spinal cord neurons.

The action of glycine and GABA on isolated lamprey spinal cord neurons was investigated by means of intracellular perfusion and concentration clamp techniques. These amino acids activated desensitizing chloride ionic conductances. The concentrations of agonists evoking half-maximum effects (ED50) were equal to 16 microM and 1.5 mM for glycine- and GABA-activated currents, respectively. Increase in the transmitter concentration led to a decrease in the time constant of desensitization. Current-voltage relationships of glycine- and GABA-activated currents were strongly dose-dependent. At low agonist concentrations the time constant of activation decreased with membrane hyperpolarization. Glycine- and GABA-activated currents exhibited complete cross-desensitization. The specific glycine antagonist, strychnine, suppressed both glycine- and GABA-activated currents to the same degree. Selective antagonists of GABA receptors, bicuculline and picrotoxin, produced equal blocking effects on glycine- as well as GABA-evoked responses. In the cells studied, taurine activated desensitizing ionic conductance. Responses evoked by taurine and glycine applications demonstrated complete cross-desensitization. Taurine-activated currents were sensitive to strychnine, bicuculline and picrotoxin. These results suggest the existence of one receptor-channel complex for the main inhibitory transmitters in lamprey spinal cord neurons. 3,4-Dioxy-L-beta-phenylalanine evoked desensitizing strychnine-sensitive ionic responses which exhibited cross-desensitization with glycine-activated currents.

Animals↗

PubMed1992

High affinity ligands for 'diazepam-insensitive' benzodiazepine receptors.

Structurally diverse compounds have been shown to possess high affinities for benzodiazepine receptors in their 'diazepam-sensitive' (DS) conformations. In contrast, only the imidazobenzodiazepinone Ro 15-4513 has been shown to exhibit a high affinity for the 'diazepam-insensitive' (DI) conformation of benzodiazepine receptors. We examined a series of 1,4-diazepines containing one or more annelated ring systems for their affinities at DI and DS benzodiazepine receptors, several 1,4-diazepinone carboxylates including Ro 19-4603, Ro 16-6028 and Ro 15-3505 were found to possess high affinities (Ki approximately 2.6-20 nM) for DI. Nonetheless, among the ligands examined, Ro 15-4513 was the only substance with a DI/DS potency ratio approximately 1; other substances had ratios ranging from 13 to greater than 1000. Ligands with high to moderate affinities at DI were previously classified as partial agonists, antagonists, or partial inverse agonists at DS benzodiazepine receptors, but behaved as 'GABA neutral' (antagonist) substances at DI. The identification of several additional high affinity ligands at DI benzodiazepine receptors may be helpful in elucidating the pharmacological and physiological importance of these sites.

Animals↗

PubMed1992

Regional distribution and kinetics of three sites on the GABAA receptor: lack of effect of portacaval shunting.

The regional distribution of binding sites on the GABAA receptor and their kinetic parameters were measured by quantitative autoradiography in brains from normal rats and rats with a portacaval shunt, a model of portal systemic encephalopathy in which GABA neurotransmission may be altered. The ligands used were [3H]flunitrazepam (a benzodiazepine-site agonist), [3H]-Ro15-1788 (a benzodiazepine-site antagonist), [3H]muscimol (a GABA-site agonist), and [35S]t-butylbicyclophosphorothionate (35S-TBPS, a convulsant that binds to a site near the chloride channel). Some brains were analyzed by computerized image analysis and three-dimensional reconstruction. The regional distribution of binding of the benzodiazepines was very similar, but the patterns obtained with [3H]muscimol and [35S]TBPS were different in many areas, suggesting a heterogeneous distribution of several subtypes of the GABAA receptor. The kinetic parameters were determined in brain regions for [3H]flunitrazepam, [3H]Ro15-1788, and [3H]muscimol. For each ligand, the Kd showed a significant heterogeneity among brain regions (at least threefold), contrary to conclusions drawn from earlier studies. In portacaval shunted rats, binding of all four ligands was essentially unchanged from that in control rats, indicating that, if there was an abnormality in GABA neurotransmission during portal systemic shunting, it was not reflected by altered binding to the main sites on the GABAA receptor.

Animals↗

PubMed1992

Inhibitory role of gamma-amino-butyric acid in the rabbit urinary bladder.

Gamma-amino-butyric acid (GABA) is an established inhibitory neurotransmitter in the central nervous system (CNS) and it has also been identified in the bladder. We have investigated in the rabbit the effect of GABA on detrusor activity. Rabbit detrusor muscle strips were made to contract by electrical stimulation of their autonomic nerves or by the addition of carbachol. The addition of GABA caused substantial inhibition of muscle contraction. GABA acts on 2 classes of receptors-GABAA and GABAB. The inhibition was mediated via the GABAB receptors as its effect was mimicked by baclofen (a GABAB agonist) and inhibited by 2-hydroxysaclofen (a GABAB receptor antagonist). Inhibition was not prevented by bicuculline (a GABAA receptor antagonist). This inhibition may be due to a direct muscle effect since the inhibition, which occurred with carbachol-induced contraction, was not abolished by the addition of tetrodotoxin. GABA, acting via the GABAB receptor, produces substantial inhibition of muscle contraction in the rabbit urinary bladder. This raises the possibility of using GABAB analogues in the treatment of detrusor instability.

Animals↗